Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists

ABSTRACT

Novel compounds that are modulators of PPAR receptors, and pharmaceutically acceptable salts, solvates and hydrates thereof, processes for making the compounds, pharmaceutical compositions containing the compounds, or pharmaceutically acceptable salts, solvates and hydrates thereof.

BACKGROUND OF THE INVENTION

[0001] Peroxisome Proliferator Activated Receptors (PPARs) are membersof the nuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include PPARα, PPARγ and PPARδ.

[0002] The PPARα receptor subtypes are rep to be activated by medium andlong-chain fatty acids. They are involved in stimulating beta-oxidationof fatty acids and with the activity of fibrates which reportedlyproduce a substantial reduction in plasma triglycerides and moderatereduction in low density lipoprotein (LDL) cholesterol. The PPARγreceptor subtypes are reportedly involved in activating the program ofadipocyte differentiation and are not involved in stimulating peroxisomeproliferation in the liver.

[0003] Diabetes is a disease in which a mammal's ability to regulateglucose levels in the blood is impaired because the mammal has a reducedability to convert glucose to glycogen for storage in muscle and livercells. In Type I diabetes, this reduced ability to store glucose iscaused by reduced insulin production. “Type II Diabetes” or “non-insulindependent diabetes mellitus” (NIDDM) is the form of diabetes which isdue to a profound resistance to insulin stimulating or regulatory effecton glucose and lipid metabolism in the main insulin-sensitive tissues,muscle, liver and adipose tissue. This resistance to insulinresponsiveness results in insufficient insulin activation of glucoseuptake, oxidation and storage in muscle and inadequate insulinrepression of lipolysis in adipose tissue and of glucose production andsecretion in liver. When these cells become desensitized to insulin, thebody tries to compensate by producing abnormally high levels of insulinand hyperinsulemia results. Hyperinsulemia is associated withhypertension and elevated body weight. Since insulin is involved inpromoting the cellular uptake of glucose, amino acids and triglyceridesfrom the blood by insulin sensitive cells, insulin insensitivity canresult in elevated levels of triglycerides and LDL which are riskfactors in cardiovascular diseases. The constellation of symptoms whichincludes hyperinsulemia combined with hypertension, elevated bodyweight, elevated triglycerides and elevated LDL is known as Syndrome X.

[0004] Current treatment for diabetes mellitus generally first involvestreatment with diet and exercise. However, compliance can be poor and asthe disease progresses treatment with hypoglycemics, typicallysulfonylureas, is often necessary. Sulfonylureas stimulate the β cellsof the liver to secrete more insulin. However, the response of the βcells eventually fails and treatment with insulin injection isnecessary. In addition, both sulfonylurea treatment and insulininjection have the life threatening side effect of hypoglycemic coma.Therefore, patients using these treatments must carefully controldosage.

[0005] Thiazolidinediones are a class of compounds which have been shownto increase the sensitivity of insulin sensitive cells. Increasinginsulin sensitivity rather than the amount of insulin in the bloodreduces the likelihood of hypoglycemic coma. Thiazolidinediones havebeen shown to increase insulin sensitivity by binding to PPARγreceptors. However, side effects associated with treatment withthiazolidinediones include weight gain, and, for troglitazone, livertoxicity.

[0006] PPARα and PPARγ receptors have been implicated in diabetesmellitus, cardiovascular disease, obesity, and gastrointestinal disease,such as, inflammatory bowel disease. There exists a need for newpharmaceutical agents which modulate these receptors to prevent, treatand/or alleviate these diseases or conditions while ameliorating sideeffects of current treatments.

SUMMARY OF THE INVENTION

[0007] The present invention is directed to compounds represented byStructural Formula I and pharmaceutically acceptable salts, solvates andhydrates thereof, and methods of making, methods of using, andpharmaceutical compositions having compounds represented by StructuralFormula I and pharmaceutically acceptable salts thereof:

[0008] In Structural Formula I, n is 2, 3, or 4. R₁ is H, a C1-C4 alkyl,phenyl or C1-C4 haloalkyl. R₂ are each, independently, H, a C1-C6 alkyl,a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl,a cycloalkyl, or together with the phenyl to which they are bound formnaphthyl or 1,2,3,4-tetrahydronaphthyl. R₃ are each, independently, H, aC1-C6 alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4alkyl, an aryl, or a cycloalkyl. R₄ is a C1-C4 alkyl. R₅ are each,independently, H, a substituted or unsubstituted aryl or a substitutedor unsubstituted heteroaryl, provided that at least one R₅ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl. R₆ is H, a C1-C4 alkyl, or an aminoalkyl. R₇ are each,independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxy, or a cycloalkyl. R₈ are each,independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, or each R₈ taken togetherwith the phenyl to which they are attached are benzodioxolyl.

[0009] The present invention is additionally directed to compoundsrepresented by Structural Formula Ia and pharmaceutically acceptablesalts, solvates and hydrates thereof, and methods of making, methods ofusing, and pharmaceutical compositions having compounds represented byStructural Formula Ia and pharmaceutically acceptable salts thereof:

[0010] In Structural Formula Ia, n is 1, 2,3, or 4. R₁ is H, a C1-C4alkyl, phenyl or C1-C4 haloalkyl. R₂ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, a cycloalkyl, or together with the phenyl to which they are boundform naphthyl or 1,2,3,4-tetrahydronaphthyl. R₃ are each, independently,H, a C1-C6 alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, acycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl. R₄ is a C1-C4 alkyl.R₅ are each, independently, H, a substituted or unsubstituted aryl or asubstituted or unsubstituted heteroaryl, provided that at least one R₅is a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl. R₆ is H, a C1-C4 alkyl, or an aminoalkyl. R₇ are each,independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxyl, heterocycle, or a cycloalkyl. R₈ are each,independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, or each R₈ taken togetherwith the phenyl to which they are attached are benzodioxolyl. R14 issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl. R15 is substituted or unsubstituted (CH₂). An especiallypreferred R14 group as shown by structure Ia, is of the formula:

[0011] Another R14 group that may be preferred is of the structure:

[0012] An especially preferred embodiment of this invention is acompound of the structure Ib

[0013] Provided by another embodiment of the present invention, arecompounds represented by Structural Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof, and methods of making,methods of using, and pharmaceutical compositions having compoundsrepresented by Structural Formula Ic and pharmaceutically acceptablesalts thereof:

[0014] In Structural Formula Ic, n, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R14 andR15 are as described herein above by Structure Ia. R16 is acidbioisosteres.

[0015] In one embodiment, the present invention relates to a method ofmodulating a peroxisome proliferator activated receptor by contactingthe receptor with at least one compound represented by StructuralFormula I, and pharmaceutically acceptable salts, solvates and hydratesthereof

[0016] In another embodiment, the present invention also relates topharmaceutical compositions which include a pharmaceutically acceptablecarrier and at least one compound represented by Structural Formula I,and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0017] In yet another embodiment, the present invention relates to amethod of making a compound represented by Structural Formula I.

[0018] The compounds of the present invention and pharmaceuticallyacceptable salts, solvates and hydrates thereof are believed to beeffective in treating Syndrome X, Type II diabetes, hyperglycemia,hyperlipidemia, obesity, coagaulopathy, hypertension, atherosclerosis,and other disorders related to Syndrome X and cardiovascular diseasesbecause they lower one or more of the following in mammals: glucose,insulin, triglycerides, fatty acids and/or cholesterol. In addition, thecompounds exhibit fewer side effects than compounds currently used totreat these conditions.

DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, alkyl groups include straight chained or branchedC₁-C₆ hydrocarbons, which are completely saturated.

[0020] As used herein the term “acid bioisosteres” has the meaning knownto the artisan and means one substituent which is a bioisostere andincludes, for example tetrazole, 3-hydroxyisoxazole,3-hydroxyisothazole, hydroxyihiadiazole, 3-hydroxy-γ-pyrones, andacylsulphonamide.

[0021] Substituted (CH₂)_(a) means that from one to four availablehydrogens of the CH₂ are independently replaced with a substituentselected from the group consisting of C₁-C₄ alkyl, benzyl, and C₁-C₄haloalkyl.

[0022] Cycloalkyl groups, as used herein, include C₃-C₈ hydrocarbons,which are completely saturated.

[0023] As used herein, aryl groups include carbocyclic aromatic ringsystems (e.g. phenyl), fused polycyclic aromatic ring systems (e.g.naphthyl and anthracenyl) and aromatic ring systems fused to carbocyclicnon-aromatic ring systems (e.g., 1,2,3,4-tetrahydronaphthyl).

[0024] Heteroaryl groups, as used herein, is an aromatic ring systemhaving at least one heteroatom such as nitrogen, sulfur or oxygen.Heteroaryl groups include thienyl (also referred to herein as“thiophenyl”), pyridyl, pyrrolyl, benzofuranyl isoxazolyl, andpyrimidinyl.

[0025] An aryl-C1-C6-alkyl group, as used herein, is an aryl substituentthat is linked to a compound by an alkyl group having from one to sixcarbon atoms.

[0026] A heteroaryl-C1-C6-alkyl group, as used herein, is a heteroarylsubstituent that is linked to a compound by an alkyl group having fromone to six carbon atoms.

[0027] A cycloalkyl-C1-C4-alkyl group, as used herein, is a cycloalkylsubstituent that is linked to a compound by an alkyl group having fromone to four carbon atoms.

[0028] An aminoalkyl group is an alkyl group having from one to sixcarbon atoms which is substituted with at least one amine represented by—NR₁₅R₁₆, in which R₁₅ and R₁₆ are each, independently, a C1-C6 alkyl orR₁₅ and R₁₆ taken together with the nitrogen to which they are attachedform a five or six membered heterocycloalkyl.

[0029] Substituents for an aryl or a heteroaryl group include halo; acarboxylic acid group; C1-C6 alkoxy; nitro; cyano; CHO; hydroxyl; aC1-C6 alkyl; a C1-C6 alkyl substituted with a carboxylic acid group;—C(O)NR₁₀R₁₁, in which R₁₀ and R₁₁ are each, independently, H or a C1-C4alkyl; and a C1-C6 alkyl substituted with one or more halo.

[0030] As described herein R14, aryl, heteroaryl substituents areindependently selected from the group consisting, H, a C1-C4 alkyl, aC1-C4 alkoxy, a halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, or acycloalkyl, and up to two selected from the group consisting of H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4 haloalkyl, C1-C4 haloalkoxy,a cycloalkyl, Heterocyclic or each R₈ taken together with the phenyl towhich they are attached are benzodioxolyl.

[0031] Heterocyclic represents an unsubstituted or substituted 5-6membered monocyclic, or 8-10 membered bicyclic heterocyclic ring andthat consists of carbon atoms and from 1 to 3 heteroatoms selected fromthe group consisting of N, O, or S. It also includes a bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom that affords a stable structure. Such Heterocyclic can beoptionally substituted with 1 to 5 substituents selected from the groupconsisting of hydrogen, halo, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy,C3-C10 cycloalkyl, trifluoromethyl, substituted phenyl, phenoxy.

[0032] Some preferred Heterocyclic are, for example, oxazolyl,isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyridyl,pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzothiazolyl, benzooxazolyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydroquinolyl, tetrahydroisoquinolyl.

[0033] In a preferred embodiment, the compounds of the presentinvention, separately or with their respective pharmaceuticalcompositions, have n is 2 as represented by Structural Formula II:

[0034] In Structural Formula II, R₁, R₂, R₃, R₅, R₆, R₇ and R₈ are asdefined for Structural Formula I.

[0035] In a more preferred embodiment, the compounds of the presentinvention, and their respective pharmaceutical compositions, have nequal to 2 and an oxazole ring which is substituted with a biphenylgroup as represented by Structural Formula III.

[0036] In Structural Formula III, R₁, R₃, R₆, R₇ and R₈ are as definedfor Structural Formula I, and each R₁₁ is, independently, H, a halo, aC1-C4 alkyl, or a C1-C4 alkoxy.

[0037] In another preferred embodiment, the compounds of the presentinvention, and their respective pharmaceutical compositions, have nequal to 2 and an oxazole ring which is substituted with a thienylphenylas represented by Structural Formula IV.

[0038] In Structural Formula IV, R₁, R₃, R₆, R₇ and R₈ arc as definedfor Structural Formula I, and each R₁₂ is, independenty H, a halo, aC1-C4 alkyl or a C1-C4 alkoxy.

[0039] In another preferred embodiment, the compounds of the presentinvention, and their respective pharmaceutical compositions, have nequal to 2 and each R₂ taken together with the phenyl ring to which theyare attached is a naphthyl. This embodiment can be represented byStructural Formula V.

[0040] In Structural Formula V, R₁, R₃, R₅, R₆, R₇ and R₈ are as definedfor Structural Formula I.

[0041] R₁ is preferably methyl or trifluoromethyl in the compoundsrepresented by Structural Formulas I, II, III, IV, V, VI, VII, VIII, IX,and X.

[0042] R₂ and R₃ in Structural Formulas I, II, III, IV, VII, IX and Xare preferably, independently, selected from the following group: H,C1-C6 alkyl, and C1-C4 alkoxy. More preferably R₂ and R₃ in StructuralFormulas I, I, II, IV, VIII, IX and X are, independently, selected fromH, propyl and methoxy.

[0043] Preferably, R₄ is selected from the following group: methyl,ethyl, and butyl in compounds represented by Structural Formulas I, II,III, IV, V, VI, VII, VIII, IX, and X. More preferably, R₄ is methyl incompounds represented by Structural Formulas I, II, III, IV, V, VI, VII,VIII, IX, and X.

[0044] In one embodiment, the phenyl substituent of the oxazole ring ofStructural Formulas I, II, V and VIII together with its R₅ substituentsor the biphenyl group of Structural Formulas III, VI, and IX togetherwith its R₁₁ substituents can be selected from the following group:

[0045] In another embodiment, the phenyl substituent of the oxazole ringof Structural Formulas I, II, V and VIII together with its R₅substituents or the thiophenylphenyl group of Structural Formulas IV,VI, and X together with its R₁₂ substituents can be selected from thefollowing group:

[0046] The phenoxy substituent together with its R₇ and R₈ substitutentsis preferably selected from the following group:

[0047] Preferably, R₇ and R₈ are H.

[0048] In a particularly preferred embodiment, the compound is selectedfrom the following group:

[0049]3-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid;

[0050]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid;

[0051]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid;

[0052]3-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid;

[0053]2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid;

[0054]2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid;

[0055]3-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid;

[0056]3-{4-[2-(2-Biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid;

[0057]3-(3-Methoxy-4-{2-[5-methyl-2-(4-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid;

[0058]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid;

[0059]2-Methyl-3-(4-{2-[5-methyl-2-(4thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-3-propyl-phenyl)-2-phenoxy-propionicacid;

[0060]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid;

[0061]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid;

[0062]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-phenoxypropionicacid;

[0063]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid;

[0064]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid;

[0065]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;

[0066]2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;

[0067]2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;

[0068]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid;

[0069]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid;

[0070]2-(3-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-y]-ethoxy}-phenyl)-propionicacid;

[0071]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-tert-butyl-phenoxy)-2-methyl-propionicacid;

[0072]2-(3-tert-Butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0073]2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0074]2-(4-Chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0075]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid;

[0076]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4chloro-phenoxy)-2-methyl-propionicacid;

[0077]2-(4-Cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0078]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid;

[0079]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid;

[0080]2-(3,4-Dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0081]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid;

[0082]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid;

[0083](R)-2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy-propionicacid;

[0084](R)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid;

[0085]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid;

[0086]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid;

[0087]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophon-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid;

[0088]2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid;

[0089]2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid;

[0090]2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid;

[0091]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid;

[0092]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid;

[0093]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid;

[0094]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid;

[0095]2-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0096]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid;

[0097]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid;

[0098]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-m-tolyloxy-propionicacid;

[0099]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;

[0100]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;

[0101]2-(4-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0102]2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid;

[0103]3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid;

[0104]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid;

[0105]2-(3-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;

[0106]2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid;

[0107]2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid;

[0108]2-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-phenyl)-propionicacid;

[0109]2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid;

[0110]2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid;

[0111]2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid; and

[0112](R)-3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid.

[0113] Prodrugs are compounds of the present invention, which havechemically or metabolically cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention which arepharmaceutically active in vivo. Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such asis (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.Particularly preferred esters as prodrugs are methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, andN,N-diethylglycolamido.

[0114] Methyl ester prodrugs may be prepared by reaction of the acidform of a compound of formula I in a medium such as methanol with anacid or base esterification catalyst (e.g., NaOH, H₂SO₄). Ethyl esterprodrugs are prepared in similar fashion using ethanol in place ofmethanol.

[0115] Morpholinylethyl ester prodrugs may be prepared by reaction ofthe sodium salt of a compound of Structural Formula I (in a medium suchas dimethylformamide) with 4-(2-chloroethyl)morphine hydrochloride(available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No.C4,220-3).

[0116] The term “pharmaceutically acceptable” means that the carrier,diluent, excipients and salt must be compatible with the otheringredients of the formulation, and not deleterious to the recipientthereof. Pharmaceutical formulations of the present invention areprepared by procedures known in the art using well known and readilyavailable ingredients.

[0117] “Effective amount” means an amount of compound according toStructural Formula I, in any polymorphic form, or a salt thereof that iscapable of producing its intended effect.

[0118] “Preventing” refers to reducing the likelihood that the recipientwill incur or develop any of the pathological conditions describedherein.

[0119] By virtue of its acidic moiety, a compound of Structural FormulaI forms salts with pharmaceutically acceptable bases. Such apharmaceutically acceptable salt may be made with a base which affords apharmaceutically acceptable cation, which includes alkali metal salts(especially sodium and potassium), alkali earth metal salts (especiallycalcium and magnesium), aluminum salts and ammonium salts, as well assalts made from physiologically acceptable organic bases such astrimethylamine, triethylamine, morpholine, pyridine, piperidine,picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine,quinine, quinoline, and basic amino acid such as lysine and arginine.These salts may be prepared by methods known to those skilled in theart.

[0120] Compounds of Structural Formula I, which are substituted with abasic group, may exist as salts with pharmaceutically acceptable acids.The present invention includes such salts. Examples of such saltsinclude hydrochlorides, hydrobromides, sulfates, methanesulfonates,nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g.(+)-tarates, (−)-tartrates or mixtures thereof including racemicmixtures], succinates, benzoates and salts with amino acids such asglutamic acid.

[0121] Certain compounds of Structural Formula I and their salts mayalso exist in the form of solvates, for example hydrates, and thepresent invention includes each solvate and mixtures thereof.

[0122] The compounds of Structural Formula I contain one or more chiralcenters, and exist in different optically active forms. When compoundsof Structural Formula I contain one chiral center, the compounds existin two enantiomeric forms and the present invention includes bothenantiomers and mixtures of enantiomers, such as racemic mixtures. Theenantiomers may be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

[0123] When a compound represented by Structural Formula I has one ormore chiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. The present invention includes each diastereoisomer ofcompounds of Structural Formula I and mixtures thereof.

[0124] Certain compounds of Structural Formula I may exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of compounds of Structural Formula I and mixtures thereof.

[0125] Certain compounds of Structural Formula I may exist inzwitterionic form and the present invention includes each zwitterionicform of compounds of Structural Formula I and mixtures thereof.

[0126] Certain compounds of Structural Formula I and their salts mayexist in more than one crystal form. Polymorphs of compounds representedby Structural Formula I form part of this invention and may be preparedby crystallization of a compound of Structural Formula I under differentconditions. For example, using different solvents or different solventmixtures for recrystallization; crystallization at differenttemperatures; various modes of cooling, ranging from very fast to veryslow cooling during crystallization. Polymorphs may also be obtained byheating or melting a compound of Structural Formula I followed bygradual or fast cooling. The presence of polymorphs may be determined bysolid probe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

[0127] The language a “therapeutically effective amount” or“pharmaceutically effective amount” is intended to include an amountwhich is sufficient to mediate a disease or condition and prevent itsfurther progression or ameliorate the symptoms associated with thedisease or condition. Such an amount can be administeredprophylactically to a patient thought to be susceptible to developmentof a disease or condition. Such amount when administeredprophylactically to a patient can also be effective to prevent or lessenthe severity of the mediated condition. Such an amount is intended toinclude an amount which is sufficient to modulate a PPAR receptor, suchas a PPARγ or PPARα receptor, which mediate a disease or condition.Conditions mediated by PPARα or PPARγ receptors include diabetesmehitus, cardiovascular disease, Syndrome X, obesity andgastrointestinal disease.

[0128] The compounds of Structural Formula I, and the pharmaceuticallyacceptable salts, solvates and hydrates thereof, have valuablepharmacological properties and can be used in pharmaceuticalpreparations containing the compound or pharmaceutically acceptablesalts, esters or prodrugs thereof, in combination with apharmaceutically acceptable carrier or diluent. They are useful astherapeutic substances in preventing or treating Syndrome X, diabetesmellitus and related endocrine and cardiovascular disorders and diseasesin human or non-human animals. Suitable pharmaceutically acceptablecarriers include inert solid fillers or diluents and sterile aqueous ororganic solutions. The active compound will be present in suchpharmaceutical compositions in amounts sufficient to provide the desireddosage amount in the range described herein. Techniques for formulationand administration of the compounds of the instant invention can befound in Remington: the Science and Practice of Pharmacy, 19^(th)edition, Mack Publishing Co., Easton, Pa. (1995).

[0129] For oral administration, the compound or salts thereof can becombined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, pills, powders, syrups, solutions, suspensions andthe like.

[0130] The tablets, pills, capsules, and the like may also contain abinder such as gum tragacanth, acacias, corn starch or gelatin;excipients such as dicalcium phosphate; a disintegrating agent such ascorn starch, potato starch, alginic acid, a lubricant such as magnesiumstearate; and a sweetening agent such as sucrose lactose or saccharin.When a dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as a fatty oil.

[0131] Various other materials may be present as coatings or to modifythe physical form of the dosage unit. For instance, tablets may becoated with shellac, sugar or both. A syrup or elixir may contain, inaddition to the active ingredient, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and a flavoring such ascherry or orange flavor. Such compositions and preparations shouldcontain at least 0.1 percent of active compound. The percentage ofactive compound in these compositions may, of course, be varied and mayconveniently be between about 2 percent to about 60 percent of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be obtained.

[0132] The active compounds can also be administered intranasally as,for example, liquid drops or spray. For oral or nasal inhalation, thecompounds for use according to the present invention are convenientlydelivered in the form of a dry powder inhaler, or an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of gelatin for use in an inhaler or insufflatormay be formulated containing a powder mix of the compound and a suitablepowder base such as lactose or starch.

[0133] For parental administration the compounds of the presentinvention, or salts thereof can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable salts of the compounds. Dispersions can alsobe prepared in glycerol, liquid polyethylene glycols and mixturesthereof in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

[0134] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that each syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against anycontamination. The carrier can be solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (e.g. glycerol,propylene glycol and liquid polyethylene glycol), propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils. The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

[0135] The compounds may also be formulated in rectal compositions suchas suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0136] In addition, to the formulations described previously, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation, for example,subcutaneously or intramuscularly or by intramuscular injection. Thus,for example, as an emulsion in an acceptable oil, or ion exchangeresins, or as sparingly soluble derivatives, for example, as sparinglysoluble salts.

[0137] The effective dosage of active ingredient employed may varydepending on the particular compound employed, the mode ofadministration, the condition being treated and the severity of thecondition being treated.

[0138] When used herein Syndrome X includes pre-diabetic insulinresistance syndrome and the resulting complications thereof, insulinresistance, non-insulin dependent diabetes, dyslipidemia, hyperglycemiaobesity, coagulopathy, hypertension and other complications associatedwith diabetes. The methods and treatments mentioned herein include theabove and encompass the treatment and/or prophylaxis of any one of orany combination of the following: pre-diabetic insulin resistancesyndrome, the resulting complications thereof, insulin resistance, TypeII or non-insulin dependent diabetes, dyslipidemia, hyperglycemia,obesity and the complications associated with diabetes includingcardiovascular disease, especially atherosclerosis.

[0139] The compositions are formulated and administered in the samegeneral manner as detailed herein. The compounds of the instantinvention may be used effectively alone or in combination with one ormore additional active agents depending on the desired target therapy.Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of Structural Formula I andone or more additional active agents, as well as administration of acompound of Structural Formula I and each active agent in its ownseparate pharmaceutical dosage formulation. For example, a compound ofStructural Formula I or thereof and an insulin secretogogue such asbiguanides, thiazolidinediones, sulfonylureas, insulin, or ccglucosidose inhibitors can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, a compound of Structural Formula I and oneor more additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

[0140] An example of combination treatment or prevention ofatherosclerosis may be wherein a compound of Structural Formula I orsalts thereof is administered in combination with one or more of thefollowing active agents: antihyperlipidemic agents; plasma HDL-raisingagents; antihypercholesterolemic agents, fibrates, vitamins, aspirin,and the like. As noted above, the compounds of Structural Formula I canbe administered in combination with more than one additional activeagent.

[0141] Another example of combination therapy can be seen in treatingdiabetes and related disorders wherein the compounds of StructuralFormula I, salts thereof can be effectively used in combination with,for example, sulfonylureas, biguanides, thiazolidinediones,α-glucosidase inhibitors, other insulin secretogogues, insulin as wellas the active agents discussed above for treating atherosclerosis.

[0142] A therapeutically effective amount of a compound of StructuralFormula I can be used for the preparation of a medicament useful fortreating Syndrome X, diabetes, treating obesity, lowering tryglyceridelevels, raising the plasma level of high density lipoprotein, and fortreating, preventing or reducing the risk of developing atherosclerosis,and for preventing or reducing the risk of having a first or subsequentatherosclerotic disease event in mammals, particularly in humans. Ingeneral, a therapeutically effective amount of a compound of StructuralFormula I (1) reduces serum glucose levels of a patient, or morespecifically HbA1c, typically by about 0.7%; (2) reduces the serumtriglyceride levels of a patient, typically by about 20%; and/or (3)increases the serum HDL levels in a patient, preferably by about 30%.

[0143] Additionally, an effective amount of a compound of StructuralFormula I and a therapeutically effective amount of one or more activeagents selected from a group consisting of: antihyperlipidemic agent,plasma HDL-raising agents, antihypercholesterolemic agents, fibrates,vitamins, aspirin, insulin secretogogues, insulin and the like can beused together for the preparation of a medicament useful for theabove-described treatments.

[0144] Preferably compounds of the invention or pharmaceuticalformulations containing these compounds are in unit dosage form foradministration to a mammal. The unit dosage form can be any unit dosageform known in the art including, for example, a capsule, an IV bag, atablet, or a vial. The quantity of active ingredient (viz., a compoundof Structural Formula I or salts thereof) in a unit dose of compositionis a therapeutically effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration which may be by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal and intranasal.

[0145] Pharmaceutical formulations of the invention are prepared bycombining (e.g., mixing) a therapeutically effective amount of acompound of the invention together with a pharmaceutically acceptablecarrier or diluent. The present pharmaceutical formulations are preparedby known procedures using well known and readily available ingredients.

[0146] In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilized solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

[0147] For the pharmaceutical formulations any suitable carrier known inthe art can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. For example, for intravenousinjection the compounds of the invention may be dissolved in at aconcentration of about 0.05 to about 5.0 mg/ml in a 4% dextrose/0.5% Nacitrate aqueous solution.

[0148] Solid form formulations include powders, tablets and capsules. Asolid carrier can be one or more substance which may also act asflavoring agents, lubricants, solubilisers, suspending agents, binders,tablet disintegrating agents and encapsulating material.

[0149] Tablets for oral administration may contain suitable excipientssuch as calcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc.

[0150] In powders the carrier is a finely divided solid which is inadmixture with the finely divided active ingredient. In tablets theactive ingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

[0151] Advantageously, compositions containing the compound ofStructural Formula I or the salts thereof may be provided in dosage unitform, preferably each dosage unit containing from about 1 to about 500mg be administered although it will, of course, readily be understoodthat the amount of the compound or compounds of Structural Formula Iactually to be administered will be determined by a physician, in thelight of all the relevant circumstances.

[0152] Powders and tablets preferably contain from about 1 to about 99weight percent of the active ingredient which is the novel compound ofthis invention. Suitable solid carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose,low melting waxes, and cocoa butter.

[0153] The following pharmaceutical formulations 1 through 8 areillustrative only and are not intended to limit the scope of theinvention in any way. “Active Ingredient”, refers to a compoundaccording to Structural Formula I or salts thereof.

Formulation I

[0154] Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium stearate 10 Total 460 mg

Formulation 2

[0155] A tablet is prepared using the ingredients below: Quantity(mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg

[0156] The components are blended and compressed to form tablets eachweighing 665 mg

Formulation 3

[0157] An aerosol solution is prepared containing the followingcomponents: Weight Active Ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00

[0158] The Active Ingredient is mixed with ethanol and the mixture addedto a portion of the propellant 22, cooled to 30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

[0159] Tablets, each containing 60 mg of Active ingredient, are made asfollows: Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

[0160] The Active Ingredient, starch and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solutioncontaining polyvinylpyrrolidone is mixed with the resultant powder, andthe mixture then is passed through a No. 14 mesh U.S. sieve. Thegranules so produced are dried at 50° C and passed through a No. 18 meshU.S. sieve. The sodium carboxymethyl starch, magnesium stearate andtalc, previously passed through a No. 60 mesh U.S. sieve, are then addedto the granules which, after mixing, are compressed on a tablet machineto yield tablets each weighing 150 mg.

Formulation 5

[0161] Capsules, each containing 80 mg of Active Ingredient, are made asfollows: Active Ingredient  80 mg Starch  59 mg Microcrystallinecellulose  59 mg Magnesium stearate  2 mg Total 200 mg

[0162] The Active Ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 mesh U.S. sieve, and filled intohard gelatin capsules in 200 mg quantities.

Formulation 6

[0163] Suppositories, each containing 225 mg of Active Ingredient, aremade as follows: Active Ingredient   225 mg Saturated fatty acidglycerides 2,000 mg Total 2,225 mg

[0164] The Active Ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

[0165] Suspensions, each containing 50 mg of Active Ingredient per 5 mldose, are made as follows: Active Ingredient 50 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.Color q.v. Purified water to total 5 ml

[0166] The Active Ingredient is passed through a No. 45 mesh U.S. sieveand mixed with the sodium carboxymethyl cellulose and syrup to form asmooth paste. The benzoic acid solution, flavor and color are dilutedwith a portion of the water and added, with stirring. Sufficient wateris then added to produce the required volume.

Formulation 8

[0167] An intravenous formulation may be prepared as follows: ActiveIngredient 100 mg Isotonic saline 1,000 ml

[0168] The solution of the above materials generally is administeredintravenously to a subject at a rate of 1 ml per minute.

[0169] Synthesis

[0170] Compounds in which the five membered ring is an oxazole have beensynthesized by three routes. Two of the synthetic routes rely on2-(bromophenyl)-4-(2-hydroxyethyl-5-substituted-oxazole intermediate(Structural Formula XVII), the synthesis of which is depicted in SchemeI.

[0171] The first step of the synthesis of the2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole intermediate isa condensation of a dionemonooxime represented by Structural Formula XIwith a bromobenzaldehyde represented by Structural Formula XII in thepresence of an acid such as aqueous concentrated hydrochloric acid or,preferably, acetic acid which is saturated with hydrogen chloride gas.Typically, hydrogen chloride is bubbled through a solution of thedionemonooxime and the bromobenzaldehyde in acetic acid, which is heldat a constant temperature of about −20° C. to about 20° C. for about 15minutes to about 1 hour. The product of the condensation is an oxazoleN-oxide represented by Structural Formula XIII.

[0172] The oxazole N-oxide is then treated with phosphorous oxychloridein an inert solvent such as dichloromethane or chloroform to form a2-(bromophenyl)-4-chloromethyl-5-substituted-oxazole represented byStructural Formula XIV. The reaction typically is carried out at thereflux temperature of the solvent used and is complete in about 15minutes to about 1 hour.

[0173] The 2-(bromophenyl)-4-chloromethyl-5-substituted-oxazole is thentreated with a cyanide and an iodide salt to form a 2-(bromophenyl)-4cyanomethyl-5-substituted-oxazole represented by Structural Formula XV.The reaction is typically carried out in a polar, aprotic solvent suchas dimethylformamide at a temperature of about 30° C. to about 120° C.for about 1 hour to about 6 hours. Preferably, the cyanide and iodidesalts are potassium cyanide and potassium iodide.

[0174] The cyano group of the a2(bromophenyl)-4-cyanomethyl-5-substituted-oxazole is converted to acarboxylic acid group by treatment with a alkali metal hydroxide to forma 2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazole represented byStructural Formula XVI. The reaction is generally carried out in anaqueous solution at about 80° C. to about 100° C. The concentration ofthe alkali metal hydroxide in the aqueous solution is typically about25% to about 85% (weight/volume). Preferably, the alkali metal hydroxideis potassium hydroxide.

[0175] The 2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazole is thentreated with a carboxylic acid reducing agent, such as borane or lithiumaluminum hydride, to form the2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole intermediaterepresented by Structural Formula XVII. The reaction is typicallycarried out under anhydrous conditions in an ether solvent such astetrahydrofuran (THF), dioxane, or ethyl ether. When borane is thereducing agent used, it typically forms a complex with the ether solventsuch as a BH₃-THF complex. A solution having a concentration of about0.5 M to about 1.5 M borane complex in the ether solvent is addeddropwise to absolution of 0.1 M to 1.3 M of the2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazole in the ethersolvent. The reaction temperature is about 20° C. to about 40° C.Typically, the reaction is complete in about 1 hour to about 5 hours.

[0176] In a first synthetic route to prepare compounds represented byStructural Formula I in which the five membered ring is an oxazole ring(see Scheme II), the intermediate represented by Structural Formula XVIIcan be converted into a 2-(bromophenyl-5-substituted-oxazol-4-yl)ethylsulfonyl ester represented by Structural Formula XVIII by treatment witha sulfonyl anhydride or a sulfonyl halide such as tosyl anhydride, mesylanhydride, tosyl chloride or mesyl chloride in the presence of a base(Scheme II, step 1). The reaction is typically carried out in an aproticsolvent such as methylene chloride in the presence of an aprotic base,such as pyridine, and in the presence of a nucleophilic catalyst, suchas N,N-dimethylaminopyridine DMAP). The reaction is complete in about0.5 hours to about 5 hours.

[0177] The 2-(bromophenyl-5-substituted-oxazol-4-yl)ethyl sulfonyl esteris then reacted with a phenol represented by Structural Formula XIX inthe presence of alkali metal carbonate to form a3-(4-{2-[2-bromophenyl)-5-substituted-oxazol-4-yl]ethoxy)-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by Structural Formula XX (Scheme II, step 2). InStructural Formula XI, R₂, R₃ and R₄ are as previously defined forStructural Formula I, and R₁₀ is a C1-C4 alkyl. The reaction istypically carried out in a polar solvent such as an alcohol at about 40°C. to about 70° C. and is allowed to proceed for about 16 hours to about30 hours. The reactants (i.e., the compounds represented by StructuralFormulas XVIII and XIX) are present in about equal molar amounts. Thealkali metal carbonate is present in about 20 molar equivalents.

[0178] Alternatively, the 2-(bromophenyl-5-substituted-oxazolylethylsulfonyl ester is then reacted with a phenol represented by StructuralFormula XIX in the presence of a hindered base to form a3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by Structural Formula XX (Scheme II, step 2). Thereaction is typically carried out in a polar solvent such as an alcoholat about 40° C. to about 70° C. and is allowed to proceed for about 24hours to about 48 hours. The reactants (i.e., the compounds representedby Structural Formulas XVIII and XIX) are present in about equal molaramounts. The alkali metal carbonate is present in about 20 molarequivalents and is preferably bound to an inert solid support such aspolystyrene.

[0179] The3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester is then treated with an aryl boronic acid in the presence oftriphenylphosphine, palladium acetate and sodium carbonate to form a3-(4-{2-[2-(arylphenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by Structural Formula XXI (Scheme II, step 3). Arin Structural Formula XXI is a substituted or unsubstituted aryl or asubstituted or unsubstituted heteroaryl. Typically, the3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester (compound XX) and the arylboronic acid are present in equalmolar amounts, or preferable about 0.1 to 0.5 molar excess of thearylboronic acid. The triphenylphosphine is present in about 1.5 toabout 2 equivalents, the palladium acetate is present in about 0.1 toabout 0.01 equivalents and the sodium carbonate is present in about 1equivalent to about 1.5 equivalents with respect to compound XX. Thereaction is generally carried out in an alcoholic solvent at about 50°C. to about 100° C. and is allowed to proceed for about 1 hour to about5 hours. Alternatively, the3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester can be treated with an aryl tributyl tin in the presence ofPd(PPh₃)₄ (“Ph” is phenyl) to form3-(4-{2-[2-(arylphenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester ester.

[0180] A second method of preparing the compounds represented byStructural Formula I which have an oxazole five membered ring isdepicted in Scheme III. The2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted oxazole represented byStructural Formula XVII is treated an arylboronic acid in the presenceof triphenylphosphine, palladium acetate (ortetrakis(triphenyl(phosphine)palladium(0)) and sodium carbonate to forma 2-(arylphenyl)-4-(2-hydroxyethyl)-5-substituted oxazole represented byStructural Formula XXII. The reaction conditions are the same as thosedescribed for step 3 in Scheme II.

[0181] The 2-(arylphenyl)-4-(2-hydroxyethyl)-5-substituted oxazole isthen treated with a sulfonyl anhydride or a sulfonyl chloride in thepresence of a base under conditions as described for step 1 of Scheme IIto form a 2-(arylphenyl-5-substituted-oxazol-4yl)ethyl sulfonyl esterrepresented by Structural Formula XXIII.

[0182] The 2-(arylphenyl-5-substituted-oxazol-4-yl)ethyl sulfonyl esteris then reacted with a phenol represented by Structural Formula XIX inthe presence of an alkali metal carbonate or a hindered base underconditions as described for step 2 of Scheme II to form a3-(4-{2-[2-(arylphenyl)-5-substituted-oxazol-4-yl]ethoxy)-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by Structural Formula XXI.

[0183] The compound represented by Structural Formula XIX can beprepared by the method depicted in Scheme IV. In this method, anabromoester represented by compound XXIV is reacted with a phenolrepresented by compound XXV to form an α-aryloxy ester represented bycompound XXVI. This reaction is typically carried out in an anhydrouspolar solvent such as DMF at a temperature of about 60° C. to about 110°C. The reaction time is about 10 h to about 20 h.

[0184] The α-aryloxy ester is then contacted with an alkyl lithiumcompound to form the enolate. This reaction is is typically performed inan anhydrous, polar, aprotic solvent at a temperature of about −20° C.to about −110° C. After about 5 min to about 20 min. a4-benzyloxybenzaldehyde represented by compound XXVII is added and thereaction is stirred for about 5 min. to about 30 min., then quenchedwith an aqueous solution of ammonium chloride or acetic acid in THF toform a 3-(4-benzyloxyphenyl)-3-hydroxy-2-substituted-2-aryloxy-propanoicester represented by Structure XXVIII.

[0185] A solution of3-(4-benzyloxyphenyl)-3-hydroxy-2-substituted-2-aryloxy-propanoic esterin an anhydrous aprotic solvent at a temperature of about −10° C. toabout 10° C. was treated with an ether complex of boron trifluoride andtriethylsilane. The reaction is gradually allowed to warm to roomtemperature then stirred for about 1 h to about 2.5 h. The mixture isquenched by adding an aqueous base to give3-(4-benzyloxyphenyl)-2-substituted-2-aryloxy-propanoic esterrepresented by Structural Formula XXIX.

[0186] The 3-(4-benzyloxyphenyl)-2-substituted-2-aryloxy-propanoic esteris treated to remove the benzyl protecting group to yield a3-phenyl-2-substituted-2-aryloxy-propanoic ester represented byStructural Formula XIX. Method for removing benzyl protecting groupsfrom a phenol are known to those skilled in the art and can be found inGreen, et al., Protective Groups in Organic Synthesis, 2^(nd) Edition,John Wiley & Sons, Inc., p. 156-158.

[0187] When aryloxy group contains electron donating group, such asalkyl, alkoxy groups,3-(4-hydroxyphenoxy)-2-substituted-2-aryloxypropanoic ester can beprepared by following method.

[0188] A solution of3-(4-benzyloxyphenyl)-3-hydroxy-2-substituted-2-aryloxy propanoic ester(XXVIII) in CH2Cl2 at 0° C. was added trifluoroacetic anhydride andpyridine. The mixture was allowed to warm up to r.t. for 2 h. Themixture was quenched by 1N HCl to give3-(4-benzyloxyphenyl)-3-trifluoroacetate-2-substituted-2-aryloxypropanoic ester (?). It can then be converted to3-(4-hydroxyophenyl)-2-substituted-2-aryloxypropanoic ester (XIX) bytreatment with 10% Pd/C under 1 atm H2 in EtOAc for 48 h.

[0189] When aryloxy group contains basic functional groups, such asamine, aniline, 3-(4-hydroxyphenoxy)-2-substituted-2-aryloxypropanoicester can be prepared by following method.

[0190] A solution of3-(4-benzyloxyphenyl)-3-hydroxy-2-substituted-2-aryloxy propanoic ester(XXVIII) in dichloroethane was added trifluoroacetic acid andtriethylsilane. The mixture was heated to reflux for 48 h. The reactioncan be quenched with saturated aqueous NaHCO₃ to give3-(4-benzyloxy-phenoxy)-2-substituted-2-aryloxypropanoic ester (XXIX).3-(4-hydroxyphenyl)-2-substituted-2-aryloxypropanoic ester (XIX) can beobtained by removal of benzyl group using method described in previouscontext.

EXAMPLES

[0191] General: Infrared spectra were recorded on a Perkin Elmer 781spectrometer. ¹H NMR spectra were recorded on a Varian 400 MHzspectrometer at ambient temperature. Data are reported as follows:chemical shift in ppm from internal standard tetramethylsilane on the δscale, multiplicity (b=broad, s=singlet, d=doublet, t=triplet,q=quartet, qn=quintet and m=multiplet), integration, coupling constant(Hz) and assignment. ¹³C NMR were recorded on a Varian 400 MHzspectrometer at ambient temperature. Chemical shifts are reported in ppmon the δ scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 7.26 ppm and DMSO-d₆ at 2.52 ppm). Combustionanalyses were performed by Eli Lilly & Company MicroanalyticalLaboratory. High resolution mass spectra were obtained on VG ZAB 3F orVG 70 SE spectrometers. Analytical thin layer chromatography wasperformed on EM Reagent 0.25 mm silica gel 60-F plates. Visualizationwas accomplished with UV light.

Example 13-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl)-2-methyl-2-phenoxypropionicacid:

[0192]

A. 2-Phenoxypropionic acid ethyl ester

[0193] Phenol (28.5 g, 0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF(1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After16 h, the DMF was removed in vacuo. The residue was dissolved in ethylacetate (300 mL) and washed twice with water and once with brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to producea golden oil (48.5 g, 83%) ¹H NMR (250 MHz, CDCl₃): δ 7.31 (d, 2H,J=7.8), 7.02 (t, 1H, J=7.9), 6.93 (d, 2H, J=7.8), 4.79 (q, 1H, J=6.1),4.26 (q, 2H, J=7.2), 1.66 (d, 3H, J=6.1), 1.24 (t, 3H, J=7.2). MS [EI+]195 (M+H)⁺

B. 2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester

[0194] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78 ° C. in a dry ice/acetone bath and then added to asolution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester (4.79 g, 24.7 mmol) in anhydrous THF (30 mL) also cooled to −78°C. under an atmosphere of nitrogen. After 5 min, 4-benzyloxybenzaldehyde(4.76 g, 22.4 mmol) was added in one portion. After stirring for 10 min,the reaction mixture 20 was quenched with saturated solution of aqueousNH₄Cl (10 mL) and the mixture allowed to warm to ambient temperature.The biphasic mixture was diluted with ether (100 mL) and partitioned,and the organic layer was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (600 g silica, 25×200 mL fractions, gradient elution0-20% ethyl acetate in hexanes) to provide a colorless oil (3.84 g, 42%)as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-phenoxy-3-hydroxy-2-methylpropionic acid ethylester which was used without further characterization or purification.R_(f)=0.32 in 4:1 hexanes:ethyl acetate.

[0195] 3-(4-Benzyloxyphenyl)-3-hydroxy-2-phenoxy-2-methylpropionic acidethyl ester (3.84 g, 9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to0° C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-phenoxy-2-methylpropionic acid ethyl ester as acolorless oil (1.34 g, 36%). R_(f)=0.90 (9:1 hexanes:ethyl acetate). ¹HNMR (300 MHz, CDCl₃): δ 7.36-7.42 (m, 3H), 7.34 (t, 1H), 7.17-7.24 (m,5H), 6.98 (t, 1H), 6.91 (d, 2H), 6.83 (d, 2H), 5.05 (s, 2H), 4.22 (q,1H, J=7.1), 3.26 (d, 1H, J=13.7), 3.13 (d, 1H, J=13.7), 1.40 (s, 3H),1.22 (t, 3H, J=7.1). MS [EI+] 408 (M+NH₄)⁺

C. 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester

[0196] 2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethylester (830 mg, 2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to a colorless oil (563 mg, 89%) ¹H NMR(300 MHz, CDCl₃): δ 7.23 (t, 2H), 7.13 (d, 2H), 6.96 (t, 1H), 6.83 (d,2H), 6.76 (d, 2H), 4.19 (q, 1H, J=7.1), 3.23 (d, 1H, J=12.4), 3.08 (d,1H, J=12.4), 1.39 (s, 3H), 1.22 (t, J=7.1). MS [EI+] 318 (M+H)³⁰, [EI−]359 (M+OAc).

[0197] 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester(approx 48 g) prepared in the same manner was purified by chiralchromatography to provided the individual enantiomers (Chiralcel OD,8×27 cm, 7% IPA/heptane, 248 nm; (S)-isomer: 97.2% ee; (R)-isomer. >99%ee).

D. 4,5-Dimethyl-2-(4-bromophenyl)-oxazole oxide

[0198] A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and4-bromo-benzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) wascooled to 0° C. and then gaseous HCl was bubbled through the solutionfor 35 min while the reaction was stirred in an ice bath. Diethyl ether(500 mL) was then added to the reaction to precipitate the product andthe resultant slurry stirred 45 min at 0° C. before being filtered. Thesolids were rinsed with Et20 (50 mL), taken up in water (1 L) and conc.NH₄OH (60 mL) added to the slurry. This mixture was extracted withCHCl₃, the organic layer was dried (MgSO₄), and the solvent removed invacuo to give 97.4 g (74%) of 4,54dimethyl-2-(4-bromophenyl)-oxazoleoxide as a white solid. The compound should be used directly within24-48 h: ¹H NMR (500 MHz, CDCl₃) 8.34 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0Hz, 2H), 2.35 (s, 3H), 2.20 (s, 3H); ¹³C (125 MHz, CDCl₃) 142.1, 131.9,129.5, 126.3, 124.1, 122.2, 11.1, 6.2; IR (KBr) 1685, 1529, 1418, 1377,1233, 1165 cm⁻¹; UV (EtOH)_(max) 307 nm (24371); HRMS (TOF) m/zcalculated for C₁₁H₁₁ ⁷⁹BrNO₂: 267.997, found 267.9951.

E. 2-(4-Bromophenyl-4-(chloromethyl)-5-methyloxazole

[0199] A solution of 4,5-dimethyl-2-(4-bromophenyl)-oxazole oxide (96.6g, 0.36 mol) in CHCl₃ (0.90 L) was treated dropwise with phosphorousoxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm andthen was stirred at reflux for 30 min. The reaction was then cooled toroom temperature and washed with water (2×1 L). The combined aqueouswashes were back extracted with CH₂Cl₂ (2×400 mL). The organic layerswere dried (MgSO₄), and the solvent removed in vacuo to give crudeproduct that was recrystallized from hot hexanes (300 mL), decanting thehot supernate away from a dark oily material. The remaining dark oil wasagitated in additional hot hexanes (200 mL) and the combined supernateswere cooled to 0° C. to crystallize the product which was isolated byfiltration to give 74.2 g (72%) of2-(4-bromophenyl-4-(chloromethyl)-5-methyloxazole as a lime-greenpowder: Rf=0.39 in 20% ethyl acetate/hexanes; ¹H NMR (500 MHz, CDCl1 ₃)7.88-7.86 (m, 2H), 7.59-7.56 (m, 2H), 4.54 (s, 2H), 2.42 (s, 3H); ¹³C(125 MHz, CDCl₃) 159.2, 146.9, 133.2, 132.0, 127.6, 126.1, 124.7, 37.1,11.5; IR (KBr) 2970, 1633,1599,1481,1401, 1258, 1117, 1008 cm³¹ ¹; UV(tOH)_(max) 281 nm ( 21349); HRMS (FAB) m/z calculated for C₁₁H₁₀⁷⁹BrClNO: 285.9634, found 285.9641; Anal. Calculated for C₁₁H₉ClBrNO: C,46.11; H, 3.17; N, 4.89; Cl, 12.37; Br, 27.88. Found C, 46.28; H 3.07;N, 4.81; Cl, 12.36; Br, 27.88.

F. 2-(4-Bromophenyl)-5-methyl-4-oxazoleacetic acid

[0200] To a solution of2-(4-bromophenyl-4-(chloromethyl)-5-methyloxazole (64.8 g, 0.23 mol) inDMF (400 mL) was added powdered potassium cyanide (22.1 g, 0.34 mol) andpotassium iodide (28.6 g, 0.17 mol) and the resultant mixture was heatedto 85° C. for 3.5 h. The reaction mixture was then cooled to roomtemperature. Potassium carbonate (5 g) was dissolved in water (800 mL)and added dropwise to the reaction to precipitate2-(4-bromophenyl-4-(cyanomethyl)-5-methyloxazole (stir vigorously 15 minfollowing addition) which was isolated by filtration and washed withwater (2×400 mL). The crude2-(4-bromophenyl-4-(cyanomethyl)-5-methyloxazole was carried on as is inthe next step without purification. ¹H NMR (300 A, CDCl₃) 7.85 (m, 2H),7.58 (m, 2H), 3.64 (s, 3H, 2.43 (s, 3H).

[0201] The crude 2-(4-bromophenyl-4-(cyanomethyl)-5-methyloxazole(assume 0.22 mol) was combined with 2-methoxyethanol (630 mL) and 85%solid KOH (74.6 g, 1.33 mol) in water (360 mL) was added to thereaction. The mixture was heated to reflux for 3 h, cooled, quenchedwith 2 M HCl (500 mL), and extracted with CH₂Cl₂. The organic layer wasdried (MgSO₄), and the solvent removed in vacuo, using toluene toazeotropically remove residual 2-methoxyethanol. The crude product (57.3g) was recrystallized from toluene (450 mL) to give 39.8 g (60%) of2-(4-bromophenyl)-5-methyl4xazoleacetic acid as an off-white powder:Rf=0.23 in 10% MeOH/CH₂Cl₂; ¹H NMR (500 MH, CDCl₃) 9.00 (br s, 1H),7.85-7.83 (m, 2H), 7.58-7.56 (m, 2H), 3.62 (s, 3H), 2.36 (s, 3H); ¹³C(125 MHz, CDCl₃) 173.8, 159.0, 146.2, 132.0, 129.1, 127.6, 125.9, 124.7,31.5, 10.2; IR (CHCl₃) 2923, 1699, 1641, 1481, 1428, 1306, 1234, 1010,829, 727 cm⁻¹; UV (EtOH)_(max) 288 nm (19626).

G. 2-(4-Bromophenyl)-5-methyl-4-oxazoleethanol

[0202] A solution of 2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid(39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise withborane-TBF complex (227 mL of a 1.0 M solution in TBF, 1.3 mol) over 2 h(reaction temperature to 35° C.). After stirring 2 h at room temperatureunder N₂, the reaction was quenched with slow addition of methanol (60mL) and stirred overnight at room temperature. The reaction was dilutedwith 1 N NaOH (50 mL) and extracted with CH₂Cl₂ (2×200 mL). The organiclayer was washed with H₂O (3×100 mL), dried (MgSO₄), and the solventremoved in vacuo to give 38.7 g of crude product that was recrystallizedfrom toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%)of 2-(4-bromophenyl)-5-methyl-4-oxazoleethanolas a white powder: Rf=0.37in 10% MeOH/CH₂Cl₂; ¹H NMR (500 MHz, CDCl₃) 7.84-7.82 (m, 2H), 7.57-7.55(m, 2H), 3.91 (q, J=5.5 Hz, 2H), 3.14 (t, J=6 Hz, OH), 2.72 (t, J=5.5Hz, 2H), 2.33 (s, 3H); ¹³C (125 MHz, CDCl₃) 158.7, 144.5, 134.2, 131.9,127.4, 126.4, 124.3, 61.8, 28.1, 10.1; IR (KBr) 3293, 2948, 1642, 15985,1480, 1472, 1401, 1053, 1003, 836, 734 cm⁻¹; V (EtOH)_(max) 290 nm(20860); Anal. Calculated for C₁₂H₁₂BrNO₂: C, 51.09; H, 4.29; N, 4.96;Br, 28.32. Found C, 51.31; H 4.06; N, 4.90; Br, 28.19.

H. 2-(4-Biphenyl)-5-methyloxazoleethanol

[0203] 2-(4-Bromophenyl)-5-methyl-4-oxazoleethanol(10.0 g, 35.0 mmol)and phenylboronic acid (4.5 g, 38.0 mmol) were dissolved in n-propanol(120 mL) before adding tniphenylphosphine (165.2 mg, 0.63 mmol),palladium acetate (46 mg, 2.1 mmol), and Na₂CO₃ (4.5 g, 42 mmoldissolved in 30 mL distilled H₂O). The solution was heated to reflux andstirred for 1.5 h. After cooling to ambient temperature, the mixture wasconcentrated under reduced pressure and then partitioned between CH₂Cl₂(100 mL) and 1N NaOH (100 mL). The aqueous phase was extracted withCH₂Cl₂ (2×50 mL) and the combined organic phases were dried (MgSO₄) andconcentrated under reduced pressure to provide2-(4-biphenyl)-5-methyl-4-oxazoleethanol (9.5 g, 97% yield) as a whitesolid which was used directly without further purification. ¹H NMR (500MHz, CDCl₃) 8.01 (d, 2H), 7.77-7.50 (m, 4H), 7.46 (m, 2H), 7.38 (m, 1H),3.91 (q, J=5.5 Hz, 2H), 3.18 (t, J=6 Hz, OH), 2.72 (t, J=5.5 Hz, 2H),2.33 (s, 3H).

I. Toluenesulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-ylethylester

[0204] To a solution of 2-(4-biphenyl)-5-methyl4-oxazoleethanol (15.8 g,56.6 mmol) in CH₂Cl₂ (250 mL) at room temperate under N₂ was addedpyridine (14.7 g, 185 mmol, 15.0 mL) and DMAP (2.03 8, 16.6 mmol)followed by portionwise addition of tosyl anhydride (24.57 g, 75.2mmol). The reaction exothermed to 32° C. and was stirred 30 min beforeadditional 2.3 of tosyl anhydride was added. The mixture was dilutedwith 100 mL of CH₂Cl₂ and stirred vigorously with 1N HCl (150 mL) for 15min, and then the organic phase was dried (MgSO₄) and filtered through apad of silica gel (100 mL, packed with CH₂Cl₂). After rinsing the silicagel with ethyl acetate (100 mL) the solution was concentrated to givetoluene-4-sulfonic acid 2-methyl2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester as a white solid(23.3 g, 95%) which was used without further purification: Rf=0.51 in60% ethyl acetatethexanes; ¹H NMR (400 Mh, CDCl₃) 7.97 (d, 2H), 7.70 (d,2H), 7.66 (t, 2H), 7.65 (d, 2H), 7.51 (t, 1H), 7.42 (d, 2H), 7.24 (d,2H), 4.37 (t, 2H), 2.88 (t, 2H), 2.37 (s, 3H), 2.26 (s, 3H).

J.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid ethyl ester

[0205] 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(495 mg, 1.7 mmol), and toluene-4-sulfonic acid2-(2-biphenylyl-5-methyl-oxazol-4-yl)-ethyl ester (2.2 mmol) and Cs₂CO₃(700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for16 h at 55° C. under an atmosphere of nitrogen. The mixture was thencooled and diluted with ethyl acetate (100 mL), and washed with waterthen brine. The organic layer was dried with Na₂SO₄ and concentrated invacuo to a viscous yellow oil. The residue was purified by flash columnchromatography (100 g silica, 60×15mL fractions, gradient elution 0-20%ethyl acetate in hexanes) to provide the title compound as a colorlessoil.

K.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid

[0206]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid ethyl ester (3.6 mmol) in McOH (7 mL) was treated with 2N NaOH (7mL) and warmed to 55° C. After 18 h, the mixture was concentrated underreduced pressure and then acidified with 5N HCl to pH=1. The solutionwas extracted with EtOAc and then the organic phases dried (Na₂SO₄),filtered and concentrated to a white solid (7%). MS [EI+] 534 (M+H)⁺,566 (M+Na)⁺, [EI−] 532 (M−H)⁺; HPLC: T=3.29 min, purity 99%.

Example 2 3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl-2-methyl-2-phenoxypropionic acid

[0207]

A. 2-(3-Bromophenyl)-4,5-dimethyloxazole-3-oxide

[0208] A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and3-bromobenzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooledto 0° C. and then gaseous HCl was bubbled through the solution for 35min while the reaction was stirred in an ice bath. Diethyl ether (500mL) was then added to the reaction to precipitate the product and theresultant slurry stirred 45 min at 0° C. before being filtered. Thesolids were rinsed with Et₂O (50 mL), taken up in water (1 L) andconcentrated NH₄OH (60 mL) added to the slurry. This mixture wasextracted with CHCl₃, the organic layer was dried (MgSO₄), and thesolvent removed in vacuo to give 97.4 g (74%) of2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide as a white solid. Thecompound should be used directly with 24-48 h.

B. 2-(3-Bromophenyl)-4-(chloromethyl)-5-methyloxazole

[0209] A solution of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide (96.6g, 0.36 mol) in CHCl₃ (0.90 L) was treated dropwise with phosphorousoxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm andthen stirred at reflux for 30 min. The reaction was then cooled to roomtemperature and washed with water (2×L). The combined aqueous washeswere back extracted with CH₂Cl₂ (2×400 mL). The organic layers weredried (MgSO₄), and the solvent removed in vacuo to give crude productthat was recrystallized from hot hexanes (300 mL), decanting the hotsupernate away from a dark oily material. The remaining dark oil wasagitated in additional hot hexanes (200 mL) and the combined supernateswere cooled to 0° C. to crystallize the product which was isolated byfiltration to give 74.2 g (72%) of2-(3-bromophenyl)-4-(chloromethyl)-5-methyloxazole as a lime-greenpowder.

C. 2-(3-Bromophenyl)-5-methyl-4-oxazoleacetic acid

[0210] To a solution of2-(3-bromophenyl)-4-(chloromethyl)-5-methyloxazole (64.8 g, 0.23 mol) inDMF (400 mL) was added powdered potassium cyanide (22.1 g, 0.34 mol) andpotassium iodide (28.6 g, 0.17 mol) and the resultant mixture heated to85° C. for 3.5 h. The reaction mixture was then cooled to roomtemperature. Potassium carbonate (5 g) was dissolved in water (800 mL)and added dropwise to the reaction to precipitate the product (stirvigorously 15 min following addition) which was isolated by filtrationand washed with water (2×400 mL). The crude[2-(3-bromophenyl)-5-methyloxazole-4-yl]-acetonitrile was carried on asis in the next step without purification

[0211] The crude [2-(3-bromophenyl)-5-methyloxazole-4-yl]-acetonitrile(assume 0.22 mol) was combined with 2-methoxyethanol (630 mL) and 85%solid KOH (74.6 g, 1.33 mol) in water (360 mL) was added to thereaction. The mixture was heated to reflux for 3 h, cooled, quenchedwith 2 M HCl (500 mL), and extracted with CH₂Cl₂. The organic layer wasdried (MgSO₄), and the solvent removed in vacuo, using toluene toazeotropically remove residual 2-methoxyethanol. The crude product (57.3g) was recrystallized from toluene (450 mL) to give 39.8 g (60%) of2-(3-bromophenyl)-5-methyl-4-oxazoleacetic acid as an off-white powder.

D. 2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol

[0212] A solution of 2-(3-bromophenyl)-5-methyl-4-oxazoleacetic acid(39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise withborane-THF complex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h(reaction temperature to 35° C.). After stirring 2 h at room temperatureunder N₂, the reaction was quenched with slow addition of methanol (60mL) and stirred overnight at room temperature. The reaction was dilutedwith 1 N NaOH (50 mL) and extracted with CH₂Cl₂ (2×200 mL). The organiclayer was washed with HO (3×100 mL), dried (MgSO₄), and the solventremoved in vacuo to give 38.7 g of crude product that was recrystallizedfrom toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%)of 2-(3-bromophenyl)-5-methyl-4-oxazoleethanol as a white powder.

E. 2-(3-Biphenyl)-5-methyl-4-oxazoleethanol

[0213] 2-(3-Bromophenyl)-5-methyl-4-oxazoleethanol (35.0 mmol) andphenylboronic acid (4.5 g, 38.0 mmol) were dissolved in n-propanol (120mL) before adding triphenylphosphine (165.2 mg, 0.63 mmol), palladiumacetate (46 mg, 2.1 mmol), and Na₂CO₃ (4.5 g, 42 mmol dissolved in 30 mLdistilled H₂O). The solution was heated to reflux and stirred for 1.5 h.After cooling to ambient temperature, the mixture was concentrated underreduced pressure and then partitioned between CH₂Cl₂ (100 mL) and 1NNaOH (100 mL). The aqueous phase was extracted with CH₂Cl₂ (2×50 mL) andthe combined organic phases were dried (MgSO₄) and concentrated underreduced pressure to provide the desired product which was used directlywithout further purification. ¹H NMR (CDCl₃) δ 6.42 (d, J=8.6 Hz, 2H),6.38 (d, J=8.6 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H),2.55 (t, J=6.0 Hz, 2H), 1.6 (m, 4H), 1.49 (s, 6H), 1.23 (t, J=7.2 Hz,3H); MS (ES+) m/e (% relative intensity) 301.1 (28), 279.2 (M⁺+1, 49),233.1 (100), 205.1 (470), 165.1 (88).

F. Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethylester

[0214] To a solution of 2-(3-biphenyl)-5-methyl-4-oxazoleethanol (31.5mmol) in CH₂Cl₂ (150 mL) at room temperature under N₂ was added pyridine(8.74 g, 110 mmol, 8.9 mL) and DMAP (0.97 g, 7.88 mmol) followed byportionwise addition of tosyl anhydride (12.7 g, 37.8 mmol). Thereaction exothermed to 32° C. and was stirred 1 h before 1N HCl (200 mL)was added. The mixture was stirred vigorously 15 min, and then theorganic phase was dried (MgSO₄) and filtered through a pad of silica gel(200 mL, packed with CH₂Cl₂). After rinsing the silica gel with ethylacetate (100 mL) the solution was concentrated to toluene-4-sulfonicacid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H),7.80 (d, J=8.0 Hz, 1H), 7.6 (m, 5H), 7.4 (m, 4H), 7.12 (d, J=8.4 Hz,2H), 4.28 (t, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.28 (s, 3H), 2.12(s, 3H); MS (ES+) m/e (% relative intensity) 436.1 (44), 435.1 (70),434.1 (M⁺+1, 100).

G.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid

[0215] Toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) wasadded to a one dram, screw-cap vial and diluted with ethanol (0.5 mL).To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (seeEx. 1, Part C) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) andpolystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6mmol/g) and the vial was tightly closed The reaction vessel was heatedin a block heater for 24-48 h at 55° C., or until TLC or MS analysisindicates the disappearance of starting materials. The suspension wasfiltered while warm and the residue washed with ethanol (1 mL). Thesolution was treated with aqueous NaOH (5N solution, 100 μl) and thevial resealed tightly. The solution was heated in a block heater at 55°C. for 3-16 h, or until MS analysis indicates the completion of thehydrolysis. The solvents are removed with a stream of nitrogen or underreduced pressure and the residue redissolved in 1 mL water. The solutionwas acidified with aqueous HCl (5N solution, 150 μl), often causingprecipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymassirected HPLC to produce the product as a white solid (25%). MS [EI+]534 (M+H)⁺, 566 (M+Na)⁺, [EI−] 532 (M−H)⁺; HPLC: T=3.26 min, purity 97%

Example 32-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid

[0216]

A. 2-(4-Thiophen-2-yl-phenyl)-5-methyl-4-oxazoleethanol

[0217] 2-(4-Bromophenyl)-5-methyl-4-oxazoleethanol(10.0 g, 35.0 mmol)(see Ex. 1, Part G) and 2-thiophenyl boronic acid (38.0 mmol) weredissolved in n-propanol (120 ml) before adding triphenylphosphine (165.2mg, 0.63 mmol), palladium acetate (46 mg, 2.1 mmol), and Na₂CO₃ (4.5 g,42 mmol dissolved in 30 mL distilled H₂O). The solution was heated toreflux and stirred for 1.5 h. After cooling to ambient temperature, themixture was concentrated under reduced pressure and then partitionedbetween CH₂Cl₂ (100 mL) and 1N NaOH (100 mL). The aqueous phase wasextracted with CH₂Cl₂ (2×50 mL) and the combined organic phases weredried (MgSO₄) and concentrated under reduced pressure to provide2-(4-thiophen-2-yl-phenyl)-5-methyl-4-oxazoleethanol.

B. Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazolyl)ethyl ester

[0218] To a solution of2-(4-thiophen-2-yl-phenyl)-5-methyl-4oxazoleethanol (56.6 mmol) inCH₂Cl₂ (250 mL) at room temperature under N₂ was added pyridine (14.7 g,185 mmol, 15.0 mL) and DMAP (2.03 g, 16.6 mmol) followed by portionwiseaddition of tosyl anhydride (24.57 g, 75.2 mmol). The reactionexothermed to 32° C. and was stirred 30 min before additional 2.3 oftosyl anhydride was added. The mixture was diluted with 100 mL of CH₂Cl₂and stirred vigorously with 1N HCl (150 mL) for 15 min, and then theorganic phase was dried (MgSO₄) and filtered through a pad of silica gel(100 mL, packed with CH₂Cl₂). After rinsing the silica gel with ethylacetate (100 mL) the solution was concentrated to givetoluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-ylethyl ester.

C.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-2-phenoxypropionicacid

[0219] Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazolyl)ethyl ester (0.132 mmol)was added to a one dram, screw-cap vial and diluted with ethanol (0.5mL). To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (seeEx. 1, Part C) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) andpolystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6mmol/g) and the vial was tightly closed. The reaction vessel was heatedin a block heater for 2448 h at 55° C., or until TLC or MS analysisindicates the disappearance of starting materials. The suspension wasfiltered while warm and the residue washed with ethanol (1 mL). Thesolution was treated with aqueous NaOH (5N solution, 100 μl) and thevial resealed tightly. The solution was heated in a block heater at 55°C. for 3-16 h, or until MS analysis indicates the completion of thehydrolysis. The solvents are removed with a stream of nitrogen or underreduced pressure and the residue redissolved in 1 mL water. The solutionwas acidified with aqueous HCl (5N solution, 150 μl), often causingprecipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymass-directed HPLC to produce the product as a white solid (24%). MS[EI+] 540 (M+H)⁺, 562 (M+Na)⁺, [EI−] 538 (M−H)⁺; HPLC: T=3.24 min,purity 100%.

Example 43-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid

[0220]

A. 2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethanol

[0221] 2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54mmol) (see Ex. 2, Part D) and para-fluorophenyl boronic acid (744 mg,5.32 mmol) were stirred in n-PrOH (10 mL) under nitrogen, to which 2MNa₂CO₃ (3.54 mL) was added. The mixture was heated at 85° C., and afterPd(PPh₃)₄ (41 mg, 0.0354 mmol) was added, the reaction proceeded for 0.5h. Once the reaction mixture had cooled to room temperature, it wasconcentrated and taken up in CH₂Cl₂ (20 mL), then washed with 0.5M NaOH(20 mL). The aqueous layer was back-extracted with CH₂Cl₂ (10 mL),combined organics were washed with 1M NaOH (10 mL), followed by H₂O (10mL), then dried over Na₂SO₄, and concentrated to a crude solid.Recrystallized from ethyl acetate:hexanes (1:1) and vacuum oven-dried at50° C. to yield a tan solid (375 mg, 36%). ¹H NMR (400 MHz, CDCl₃) δ8.17 (s, 1H), 7.96 (d, J=7.6 Hz, 1H) 7.63-7.59 (m, 3H), 7.50 (t, J=7.6Hz, 1H), 7.18-7.13 (m, 2H) 3.95 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz,2H), 2.37 (s, 3H); MS (EI) 298.1 (M+H)⁺.

B. Toluene-4-sulfonic acid2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethyl ester

[0222] To a solution of2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethanol(11.6 mmol) inCH₂Cl₂ (46 mL) at room temperature under N₂ was added pyridine (3.28 mL)and DMAP (0.43 g, 3.48 mmol) followed by portionwise addition of tosylanhydride (4.54 g, 13.9 mmol). The reaction exothermed to 32° C. and wasstirred 2 h before IN HCl (50 mL) was added. The mixture was stirredvigorously 15 min, and then the organic phase was dried (MgSO₄) and thenconcentrated under reduced pressure. The residue was purified by columnchromatography (40 mL SiO₂, 50% EtOAc/hexanes) to providetoluene-4-sulfonic acid2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethyl ester: ¹H NMR(400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.4Hz, 2H), 7.63-7.59 (m, 3H), 7.50 (t, J=7.6 Hz, 1H), 7.19-7.14 (m, 4H),4.33 (t, J=6.4 Hz, 2H), 2.86 (t, J=6.4 Hz, 2H), 2.33 (s, 3H), 2.19 (s,3H); MS (EI) 452.1 (M+H)⁺.

C.3-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid ethyl ester

[0223] 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethyl ester (2.2 mmol)and Cs₂CO₃ (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) andstirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixturewas then cooled and diluted with ethyl acetate (100 mL), and washed withwater then brine. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo to a viscous yellow oil. The residue was purifiedby flash column chromatography (100 g silica, 60×15 mL fractions,gradient elution 0-20% ethyl acetate in hexanes) to provide the titlecompound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.17 (m,1H), 7.96-7.94 (m, 1H), 7.62-7.57 (m, 3H), 7.51-7.47 (m, 1H), 7.23-7.11(m, 2H), 7.16-7.11 (m, 3H), 6.98-6.94 (m, 1H), 6.84-6.81 (m, 4H),6.78-6.75 (m, 1H), 4.24 (t, J=6.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.26(d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H),2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) 580.2 (M+)⁺.

D.3-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy)phenyl)-2-methyl-2-phenoxypropionicacid

[0224]3-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid ethyl ester (3.6 mmol) in MeOH (7 mL) was treated with 2N NaOH (7mL) and warmed to 55° C. After 18 h, the mixture was concentrated underreduced pressure and then acidified with 5N HCl to pH=1. The solutionwas extracted with EtOAc and then the organic phases dried (Na₂SO₄),filtered and concentrated to a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.18, (s, 1H), (d, J=7.6 Hz, 1H), 7.62-7.58 (m, 3H),7.48 (t, J=7.6 Hz,1H), 7.24-7.03 (m, 7H), 6.90 (t, J=8.4 Hz, 2H), 6.83 (t, J=8.4 Hz, 2H),4.22 (t, J=6.8 Hz, 2H), 3.25 (d, J=14.0 Hz, 1H), 3.15 (d, J=14.0 Hz,1H), 3.01 (t, J=6.8 Ha, 2H), 2.40 (s, 3H), 1.42 (s, 3H); MS (EI) 552.3(M+H)⁺, 550.3 (M−H)⁻.

Example 52-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid:

[0225]

A. 2-[5-Methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-ylethanol

[0226] 2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54mmol) (see Ex. 2, Part D) and 2-thiophene boronic acid (5.32 mmol) werestirred in n-PrOH (10 mL) under nitrogen, to which 2M Na₂CO₃ (3.54 mL)was added. The mixture was heated at 85° C., and after Pd(PPh₃)₄ (41 mg,0.0354 mmol) was added, the reaction proceeded for 0.5 h. Once thereaction mixture had cooled to room temperature, it was concentrated andtaken up in CH₂Cl₂ (20 mL), then washed with 0.5M NaOH (20 mL). Theaqueous layer was back-extracted with CH₂Cl₂ (10 mL), combined organicswere washed with 1M NaOH (10 mL), followed by H₂O (10 mL), then driedover Na₂SO₄, and concentrated to a crude solid. Recrystallized fromethyl acetate:hexanes (1:1) and vacuum oven-dried at 50° C. to yield atan solid. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.91 (d, J=8.0 Hz,1H), 7.66 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H),7.42 (dd, J=3.6 Hz,J=0.8 Hz, 1H), 7.32 (dd, J=5.2 Hz, J=0.8 Hz, 1H), 7.12 (dd, J=5.2 Hz,J=3.6 Hz 1H), 3.95 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.37 (s,3H); MS (EI) 286.1 (M+H)⁺.

B. Toluenesulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester

[0227] To a solution of2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-ylethanol (11.6 mmol) inCH₂Cl₂ (46 mL) at room temperature under N₂ was added pyridine (3.28 mL)and DMAP (0.43 g, 3.48 mmol) followed by portionwise addition of tosylanhydride (4.54 g, 13.9 mmol). The reaction exothermed to 32° C. and wasstirred 2 h before 1N HCl (50 mL) was added. The mixture was stirredvigorously 15 min, and then the organic phase was dried (MgSO₄) and thenconcentrated under reduced pressure. The residue was purified by columnchromatography (40 mL SiO₂, 50% EtOAc/hexanes) to providetoluenesulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4yl]ethyl ester: ¹H NMR (400MHz, CDCl₃) δ 8.10 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.66 (d, J=8.4 Hz,2H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.41 (dd, J=4.0 Hz,J=1.2 Hz, 1H), 7.33 (dd, J=5.2 Hz, J=1.2 Hz, 1H), 7.17 (d, J=8.4 Hz,2H), 7.12 (dd, J=4.0 Hz, J=5.2 Hz, 1H), 4.33 (t, J=6.2 Hz, 2H), 2.84 (t,J=6.2 Hz, 2H), 2.33 (s, 3H), 2.17 (s, 3H); MS (EI) 440.1 (M+H)⁺.

C.2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid ethyl ester

[0228] 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (2.2 mmol)and Cs₂CO₃ (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) andstirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixturewas then cooled and diluted with ethyl acetate (100 mL), and washed withwater then brine. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo to a viscous yellow oil. The residue was purifiedby flash column chromatography (100 g silica, 60×15 mL fractions,gradient elution 0-20% ethyl acetate in hexanes) to provide the titlecompound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H),7.90 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H),7.42-7.41 (m, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.23-7.09 (m, 5H), 6.96 (t,J=7.2 Hz, 1H), 6.85-6.81 (m, 4H), 4.25 (t, J=6.8 Hz, 2H), 7.20 (q, J=7.2Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t,J=6.8 Hz, 2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI)568.2 (M+H)⁺. D.2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid

[0229]2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophon-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid ethyl ester (3.6 mmol) in MeOH (7 mL) was treated with 2N NaOH (7mL) and warmed to 55° C. After 18 h, the mixture was concentrated underreduced pressure and then acidified with 5N HCl to pH=1. The solutionwas extracted with EtOAc and then the organic phases dried (Na₂SO₄),filtered and concentrated to a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.09 (s, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.62-7.59(m, 2H), 7.53 (t, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.17-7.16 (m,1H), 7.13 (d, J=8.8 Hz, 2H), 6.93 (t, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz,2H), 6.79 (d, J=8.8 Hz, 2H), 4.19 (t, J=6.4 Hz, 2H), 3.16 (d, J=13.6 Hz,1H), 3.04 (d, J=6.4 Hz, 1H), 2.93 (t, J=6.4 Hz, 2H), 2.49-2.48 (m, 2H),2.36 s, 3H),1.26 (s, 3H); MS (EI) 540.1 (M+H)⁺, 538.2 (M−H)⁻.

Example 62-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid

[0230]

A. 2-[5-Methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethanol

[0231] 2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54mmol) (see Ex. 2, Part D) and 3-thiophene boronic acid (5.32 mmol) werestirred in n-PrOH (10 mL) under nitrogen, to which 2M Na₂CO₃ (3.54 mL)was added. The mixture was heated at 85° C., and after Pd(PPh₃)₄ (41 mg,0.0354 mmol) was added, the reaction proceeded for 0.5 h. Once thereaction mixture had cooled to room temperature, it was concentrated andtaken up in CH₂Cl₂ (20 mL), then washed with 0.5M NaOH (20 mL). Theaqueous layer was back-extracted with CH₂Cl₂ (10 mL), combined organicswere washed with 1M NaOH (10 mL), followed by H₂O (10 mL), then driedover Na₂SO₄, and concentrated to a crude solid. Recrystallized fromethyl acetate:hexanes (1:1) and vacuum oven-dried at 50° C. to yield atan solid. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.92 (d, J=8.0 Hz,1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J=8.0 Hz, 1H)7.46(m, 1H), 7.41 (m, 1H), 3.95 (t, J=5.6 Hz, 2H), 2.74 (t, J=5.6 Hz,1H), 2.36 (s, 3H); MS (EI) 286.1 (M+H)⁺.

B. Toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethyl ester

[0232] To a solution of2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-ylethanol (11.6 mmol) inCH₂Cl₂ (46 mL) at room temperature under N₂ was added pyridine (3.28 mL)and DMAP (0.43 g, 3.48 mmol) followed by portionwise addition of tosylanhydride (4.54 g, 13.9 mmol). The reaction exothermed to 32° C. and wasstirred 2 h before 1N HCl (50 mL) was added. The mixture was stirredvigorously 15 min, and then the organic phase was dried (MgSO₄) and thenconcentrated under reduced pressure. The residue was purified by columnchromatography (40 mL SiO₂, 50% EtOAc/hexanes) to providetoluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4yl]ethyl ester: ¹H NMR (400MHz, CDCl₃) δ 8.11 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.4 Hz,2H), 7.64 (m, 1H), 7.56-7.44 (m, 1H), 7.48-7.42 (m, 3H), 7.17 (d, J=8.4Hz, 2H), 4.33 (t, J=6.2 Hz, 2H), 2.84 (t, J=6.2 Hz, 2H), 2.33 (s, 3H),2.18 (s, 3H); MS (EI) 440.1 (M+H)⁺.

C.2-Methyl-3-≡2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid ethyl ester

[0233] 3-(4Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4yl]ethyl ester (2.2 mmol)and Cs₂CO₃ (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) andstirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixturewas then cooled and diluted with ethyl acetate (100 mL), and washed withwater then brine. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo to a viscous yellow oil. The residue was purifiedby flash column chromatography (100 g silica, 60×15 mL fractions,gradient elution 0-20% ethyl acetate in hexanes) to provide the titlecompound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H),7.90 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.64 (dt, J=7.6 Hz, J=1.2 Hz, 1H),7.56-7.55 (m, 1H), 7.48-7.39 (m, 3H), 7.23-7.14 (m, 5H), 6.96 (t, J=7.2Hz, 1H), 6.83-6.81 (m, 4H), 4.24 (t, J=6.8 Hz, 2H), 4.12 (q, J=7.2 Hz,2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t, J=6.4Hz, 2H), 2.39 (s, 3H), 1.38 (s, 3H) 1.21 (t, J=7.2 Hz, 3H); MS (EI)568.2 (M+H)⁺.

D.2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid

[0234]2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid ethyl ester (3.6 mmol) in MeOH (7 mL) was treated with 2N NaOH (7mL) and warmed to 55° C. After 18 h, the mixture was concentrated underreduced pressure and then acidified with 5N HCl to pH=1. The solutionwas extracted with EtOAc and then the organic phases dried (Na₂SO₄),filtered and concentrated to a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ8.15 (t, J=1.6 Hz, 1H), 7.98 (dd, J=2.8 Hz, J=1.6 Hz, 1H), 7.82-7.79(m, 2H), 7.66 (dd, J=7.6 Hz, J=2.8 Hz, 1H), 7.59 (dd, J=6.4 Hz, J=1.2Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.24 (t, J=8.0 Hz, 2H), 7.13 (d, J=8.4Hz, 2H), 6.93 (t, J=7.6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.79 (dd, J=7.6Hz, J=1.2 Hz, 2H), 4.19 (t, J=6.4 Hz, 2H), 3.16 (d, J=13.2 Hz, 1H), 3.04(d, J=13.2 Hz, 1H), 2.92 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.26 (s, 3H);MS (EI) 540.2 (M+H)⁺, 538.3 (M−M)⁻.

Example 73-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid

[0235]

A. 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionicacid

[0236] A stirred solution of LDA in cyclohexane (1.5 M) was cooled to−20° C., to which a solution of 2-phenoxypropionic acid (10 g, 60.2mmol) in TBF (80.3 mL) was slowly added, keeping the temperature below−10° C. The resulting dianion solution was stirred for 15 min, then asolution of 4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) inTHF (80.3 mL) was added over 1 h, maintaining temperature below −10° C.Fifteen minutes after completion of aldehyde addition, the reactionmixture was poured onto ice water (200 mL), and extracted using 1:2Et₂O:hexane (500 mL). The aqueous layer was isolated, extracted againwith 1:2 Et₂O:hexane (240 mL), then acidified with concentrated HCluntil pH=3. The product acid was extracted into ethyl acetate (2×165mL), which was dried over Na₂SO₄ and concentrated to an orange paste(16.5 g crude, 67%): MS (EI) 426.2 (M+NH₄)⁺, 407.2 (M−H)⁻.

B. 3-(4-Benzyloxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid

[0237] A stirred solution of Et₃SiH (8.67 mL, 54.3 mmol) in CH₂Cl₂ (45mL) was treated with BF₃.Et₂O (6.8 mL, 54.3 mmol).3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionicacid (7.39 g, 18.1 mmol) in CH₂Cl₂ (90.5 mL) was then added dropwise viaaddition funnel, maintaining temperature below −7° C. After the additionwas complete, the reaction was stirred for 1.5 h at −10° C., thenquenched with 1 M NaOH (18.1 mL) and diluted with H₂O (12 mL). 1N HClwas used to adjust pH to 4, followed by separation of layers. Theaqueous layer was extracted with CH₂Cl₂ (2×15 mL), and combined organiclayers were washed first with 1N HCl (15 mL), then H₂O (15 mL), followedby drying over Na₂SO₄ and concentration to a gummy orange solid (6.86 g,97%): MS (EI) 410.2 (M 30 NH₄)⁺, 391.3 (M−H)⁻.

C. 3-(4-Hydroxy-3-methoxy-phenyl)-2-methyl-2-phenoxypropionic acid

[0238] A solution of3-(4-benzyloxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid (6.86g, 17.5 mmol) in EtOH (175 mL) was added to 5% Pd/C (186 mg, 10 wt %).The mixture was purged first with nitrogen, then with H₂, which was thenapplied at 45 p.s.i. for 2 h. Pd/C was subsequently filtered off throughcelite, and the filtrate was concentrated to a crude oil (5.42 g, inexcess of theory). MS (EI) 301.2 (M−H)⁻.

D. 3-(4-Hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester

[0239] A solution of3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxy-propionic acid (4.56 g,15.08 mmol) in EtOH (150 mL) was treated with SOCl₂ and heated at 75° C.for 14 h, then cooled to room temperature and partitioned between ethylacetate (300 mL) and H₂O (400 mL). The aqueous layer was removed andback-extracted with ethyl acetate (100 mL). Combined organic phases werewashed with 10% Na₂CO₃, which was isolated and back-extracted with EtOAc(100 mL). Combined organic phases were washed with brine (200 mL), driedover Na₂SO₄, concentrated, and purified by column chromatography (200 gSiO₂, 1:4 ethyl acetate:hexanes) to provide a colorless oil, whichdeveloped a green color over a 24-hour period. The material was taken upin ethyl acetate and filtered through celite, then concentrated to yielda colorless oil (1.99 g, 40%): Rf=0.40 in 1:4 ethyl acetate:hexanes; ¹HNMR (400 MHz, CDCl₃) δ 7.66-7.55(m, 1H), 7.25-7.21 (m, 2H), 6.99-6.92(m, 1H) 6.84-6.79 (m, 3H), 6.74-6.71 (m, 1H), 5.54 (s, 1H), 4.22 (q,J=6.8 Hz, 2H), 3.84 (s, 3H), 3.30 (d, J=14 Hz, 1H), 3.07 (d, J=14 Hz,1H), 1.40 (s, 3H), 1.23 (t, J=6.8 Hz, 3H).

E.3-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid

[0240] Toluenesulfonic acid2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (seeEx. 1, Part I) was added to a one dram, screw-cap vial and diluted withethanol (0.5 mL). To this solution are added3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) andpolystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6mmol/g) and the vial was tightly closed. The reaction vessel was heatedin a block heater for 24-48 h at 55° C., or until TLC or MS analysisindicates the disappearance of starting materials. The suspension wasfiltered while warm and the residue washed with ethanol (1 mL). Thesolution was treated with aqueous NaOH (5N solution, 100 μl) and thevial resealed tightly. The solution was heated in a block heater at 55°C. for 3-16 h, or until MS analysis indicates the completion of thehydrolysis. The solvents are removed with a stream of nitrogen or underreduced pressure and the residue redissolved in 1 mL water. The solutionwas acidified with aqueous HCl (5N solution, 150 μl), often causingprecipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified by massdirected HPLC to provide analytically pure material. MS (EI) 564.4(M+H)⁺.

Example 83-{4-[2-(2-Biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid

[0241]

[0242] Toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (seeEx. 2, Part F) was added to a one dram, screw-cap vial and diluted withethanol (0.5 mL). To this solution are added3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester (see Ex. 7, Part D) (0.5 mL of a 0.264 M solution in ethanol,0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene(100-125 mg, 2.6 mmol/g) and the vial was tightly closed. The reactionvessel was heated in a block heater for 24-48 h at 55° C., or until TLCor MS analysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl)and the vial resealed tightly. The solution was heated in a block heaterat 55° C. for 3-16 h, or until MS analysis indicates the completion ofthe hydrolysis. The solvents are removed with a steam of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (1N solution, 150 μl), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymass-directed HPLC to provide analytically pure material. MS (EI) 564.4(M+H)⁺.

Example 93-(3-Methoxy-4-{2-[5-methyl-2-(4-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid

[0243]

[0244] Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.132mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial anddiluted with ethanol (0.5 mL). To this solution are added3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester(see Ex. 7, Part D) (0.5 mL of a 0.264 M solution in ethanol, 0.132mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel washeated in a block heater for 24-48 h at 55° C., or until TLC or MSanalysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl)and the vial resealed tightly. The solution was heated in a block heaterat 55° C. for 3-16 h, or until MS analysis indicates the completion ofthe hydrolysis. The solvents are removed with a stream of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (5N solution, 150 μL), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymass-directed HPLC to provide analytically pure material. MS (EI) 570.4(M+H)⁺.

Example 103-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid

[0245]

A. 3-(4-Allyloxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester

[0246] A solution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (500 mg, 1.67 mmol) in methyl ethyl ketone (6 mL) wastreated with allyl bromide (232 mg, 1.92 mmol, 0.17 mL) and potassiumcarbonate (311 mg, 2.25 mmol) and then heated to reflux. After 18 h, themixture was cooled to ambient temperature and then partitioned betweenethyl acetate and water. The aqueous phase was extracted with ethylacetate and then the organic phases were dried (MgSO₄), filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (100 mL SiO₂, hexanes to 10% ethyl acetate/hexanes) toprovide the desired product (478 mg, 84%) as a clear, colorless oil: ¹HNMR (400 MHz, CDCl₃) δ 7.22 (t, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H),6.97 (dt, J=7.6, 1.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 2H), 6.84 (t, J=8.4 Hz,2H), 6.05 (ddd, J=17.2, 10.6, 5.2 Hz, 1H), 5.41 (dd, J=17.2, 1.6 Hz,1H), 5.28 (dd, J=10.8, 1.4 Hz, 1H), 4.22 (d, J=5.2 Hz, 2H), 4.19 (q,J=6.8 Hz, 2H), 3.27 (A of AB, J=14 Hz, 1H), 3.11 (B of AB, J=14 Hz, 1H),1.40 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).

B. 3-(3-Allyl-4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethylester

[0247] A solution of 3-(4-allyloxyphenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (475 mg, 1.39 mmol) in dimethylaniline (1.5 mL) washeated at reflux for 18 h. After cooling to ambient temperature, thereaction mixture was partitioned between ethyl acetate and 1N H₂SO₄. Theorganic phase was dried (MgSO₄), filtered and concentrated. The residuewas purified by column chromatography (100 mL SiO₂, hexanes to 30% ethylacetate/hexanes) to provide the desired product (343 mg, 72%) as a paleyellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t, J=8.4 Hz, 2H), 7.02-6.96(m, 3H), 6.83 (d, J=8.8 Hz, 2H), 6.72 (d, J=7.6 Hz, 1H), 6.05 (m, 1H),5.16-5.09 (m, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.38 (d, J=6.4 Hz, 2H), 3.25(A of AB, J=13.6 Hz, 1H), 3.10 (B of AB, J=13.6 Hz, 1H), 1.41 (s, 3H),1.23 (t, J=6.8 Hz, 3H).

C. 3-(4-Hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethylester

[0248] A solution of3-(3-allyl-4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethylester(330 mg, 0.97 mmol) in absolute ethanol ( 5 mL) was treated with 5%Pd/C and then the mixture was evacuated thee times with N₂. The reactionmixture was hydrogenated at 1 atm with an H₂-filled balloon for 24 hbefore filtering the mixture over celite and rinsing with ethanol. Theproduct was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ7.22 (t, J=7.6 Hz, 2H), 7.99-6.95 (m, 3H), 6.82 (m, 2H), 6.68 (d, J=8.0Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 3.24 (A of AB, J=13.6 Hz, 1H), 3.08 (Bof AB, J=13.6 Hz, 1H), 2.55 (t, J=7.6 Hz, 2h), 1.62 (sextet, J=7.6 Hz,2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

D.3-(4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester

[0249] A solution of3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethylester (266 mg, 1.0 mmol) in DMF (10 mL) was treated with cesiumcarbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (520 mg, 1.20 mmol)(see Ex. 2, Part F) and then heated at 55° C. for 18 h. After cooling toambient temperature, the mixture was partitioned between ethyl acetateand water. The aqueous phase was extracted with ethyl acetate and thenthe organic phases were dried (MgSO₄), filtered and concentrated underreduced pressure. The residue was purified by column chromatography (100mL SiO₂, hexanes to 30% ethyl acetatelhexanes) to provide the desiredproduct (315 mg, 60%) as a clear, colorless oil: ¹H NMR (400 MHz, CDCl₃)δ 8.24 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.68-7.63 (m, 3H), 7.51 (t,J=7.6 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.38 (t, J=7.2 Hz, 1H), 7.25-7.21(m, 2H), 7.04-6.96 (m, 3H), 6.85-6.69 (m, 3H), 4.26 (t, J=6.4 Hz, 2H),4.21 (q, J=6.8 Hz, 2H), 3.26 (A of AB, J=13.6 Hz, 1H), 3.09 (B of AB,J=13.6 Hz, 1H), 3.01 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.41 (s,3H), 1.54 (sextet, J=7.6 Hz, 2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H),0.91 (t, J=7.2 Hz, 3H); MS (EI) 604.3 (M+H)⁺.

E.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid

[0250] A solution of3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-3-propyl-phonyl}-2-methyl-2-phenoxy-propionicacid ethyl ester in ethanol (1.5 mL) was treated with 5 N NaOH (140 mL)and then warmed to 65° C. After 18 h, the mixture was acidified to pH=1with 5 N HCl. The mixture was extracted with ethyl acetate and then thecombined organic phases were dried (MgSO₄), filtered and concentratedunder reduced pressure to yield the desired product (61 mg, 91%) as apale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.95 (d, J=7.6Hz, 1H), 7.65 (d, J=7.6 Hz, 3H), 7.50-7.36 (m, 4H), 7.20 (t, J=8.4 H,2H), 7.06-6.89 (m, 5H), 6.74 (d, J=8.0 Hz, 1H), 4.21 (t, J=6.4 Hz, 2H),3.27 (A of AB, J=13.6 Hz, 1H), 3.12 (B of AB, J=13.6 Hz, 1H), 3.03 (t,J=6.4 Hz, 2H), 2.51 (t, J=7.6 Hz, 2H), 2.41 (s, 3H), 1.51 (sextet, J=7.6Hz, 2H), 1.41 (s, 3H), 0.88 (t, J=7.2 Hz, 3H).

Example 112-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-3-propyl-phenyl)-2-phenoxy-propionicacid

[0251]

A.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-3-propyl-phenyl)-2-phenoxy-propionicacid

[0252] Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (see Ex.3, Part B) (0.132 mmol) was added to a one dram, screw-cap vial anddiluted with ethanol (0.5 mL). To this solution are added3-(4hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethylester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 10,Part C) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene(100-125 mg, 2.6 mmol/g) and the vial was tightly closed. The reactionvessel was heated in a block heater for 24-48 h at 55° C., or until TLCor MS analysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl)and the vial resealed tightly. The solution was heated in a block heaterat 55 ° C. for 3-16 h, or until MS analysis indicates the completion ofthe hydrolysis. The solvents are removed with a stream of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (5N solution, 150 μl), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymass-directed HPLC to provide analytically pure material. MS (EI) 582.1(M+H)⁺; LC RT=3.56 min (>99% pure).

Example 123-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid

[0253]

A. 2-Phenoxy-3-(4-benzyloxynaphthalen-1-yl)-2-methylpropionic acid ethylester

[0254] A solution of lithium diisopropyl amide (LDA) (3.5 mL, 5.2 mmol,1.5M in cyclohexane) was added dropwise slowly to a solution of3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (1.0 g,5.2 mmol) in anhydrous THF (10 mL) which was cooled to −78° C. under anatmosphere of nitrogen. After ten min4-benzyloxynaphthalene-1-carbaldehyde (1.23 g, 4.7 mmol) in anhydrousTHF (5 mL) was added dropwise. After stirring for 30 min, the reactionmixture was quenched with saturated solution of aqueous NH₄Cl (10 mL)and the mixture allowed to warm to ambient temperature. The biphasicmixture was diluted with ether (20 mL) and partitioned, and the organiclayer was washed with brine, dried over MgSO₄ and concentrated in vacuoto provide a viscous golden oil (1.80 g, 81%) as a mixture ofinseparable diastereomers of3-(4-benzyloxynaphthalen-1-yl)-2-phenoxy-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification. R_(f) (7:3 hexanes:ethyl acetate)=0.51

[0255]3-(4Benzyloxynaphthalen-1-yl)-2-phenoxy-3-hydroxy-2-methylpropionic acidethyl ester (1.80 g, 3.9 mmol) in anhydrous CH₂Cl₂ (20 mL) was cooled to0° C. and treated with BF₃-Et₂O (0.48 mL, 3.9 mmol, d=1.154) andtriethylsilane (0.63 mL, 3.9 mmol, d=0.728). The mixture was stirred for2 hr, gradually warming to ambient temperature. Saturated aqueous Na₂CO₃(15 mL) was added and the mixture was stirred vigorously for 15 min. Thesolution was partitioned and the organic layer was washed twice withwater and brine, dried over Na₂SO₄, and concentrated in vacuo to3-(4-benzyloxynaphthalen-1-yl)-2-phenoxy-2-methylpropionic acid ethylester as a golden oil (1.55 g, 89%). R_(f)=0.41 (9:1 hexanes:ethylacetate). ¹H NMR (300 MHz, CDCl₃): δ 8.33 (d, 1H, J=8.3), 8.11 (d, 1H,J=8.3), 7.47 (d, 2H, J=7.8), 7.40 (t, 1H, J=8.3), 7.37 (t, 1H, J=8.3),7.36 (t, 2H, J=7.8) 7.28 (d, 2H, J=7.8), 7.11 (t, 2H, J=8.8), 6.87 (t,1H, J=7.8), 6.79 (d, 1H, J=7.8), 6.69 (d, 2H, J=8.8), 5.18 (s, 2H, 4.08(q, 2H, J=7.0), 3.66 (d, 1H, J=14.4), 3.54 (d, 1H, J=14.4), 1.38 (s,3H), 1.13 (t, 3H, J=7.0). MS [EI+] 458 (M+NH₄)⁺

B. 2-Phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester

[0256] 2-Phenoxy-3-(4benzyloxynaphthalen-1-yl)-2-methylpropionic acidethyl ester (1.55 g, 3.5 mmol) was dissolved in ethyl acetate (50 mL)and treated with 5% palladium on carbon (400 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to a golden oil (1.20 g, 98%) ¹H NMR(300 MHz, CDCl₃): δ 8.14 (d, 1H, J=8.3), 8.10 (d, 1H, J=8.3), 7.46 (t,1H, J=8.3), 7.42 (t, 1H, J=8.3), 7.21 (d, 1H, J=7.8), 7.12 (dd, 2H,J=8.8, 7.4), 6.87 (t, 1H, J=7.4), 6.70 (m, 3H), 4.05 (q, 2H, J=6.8),3.65 (d, 1H, J=14.2), 3.54 (d, 1H, J=14.2), 1.37 (s, 3H), 1.17 (t, 3H,J=6.8). MS [EI+] 373 (M+Na)⁺, [EI−] 349 (M−H).

C.3-{4-[2-(2-Phenyl-5-methyloxazol-4-yl)ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid ethyl ester

[0257] Toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.132 mmol) (seeEx. 1, Part I) was added to a one dram, screw-cap vial and diluted withethanol (0.5 mL). To this solution are added2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (0.5 mLof a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6 mmol/g) and thevial was tightly closed. The reaction vessel was heated in a blockheater for 24-48 h at 55° C., or until TLC or MS analysis indicates thedisappearance of starting materials. The suspension was filtered whilewarm and the residue washed with ethanol (1 mL). The solution wastreated with aqueous NaOH (5N solution, 100 μl) and the vial resealedtightly. The solution was heated in a block heater at 55° C. for 3-16 h,or until MS analysis indicates the completion of the hydrolysis. Thesolvents are removed with a stream of nitrogen or under reduced pressureand the residue dissolved in 1 mL water. The solution was acidified withaqueous HCl (5N solution, 150 μl), often causing precipitation ofproduct. The suspension was diluted with dichloromethane (3 mL) and theresultant biphasic solution was filtered through a Chrom-Elut column toremove water. The filtrate was concentrated in vacuo and the resultantresidue was purified by mass-directed HPLC to produce a white solid(2%). MS [EI+] 584 (M+H)⁺, [EI−] 582 (M−H)⁺

Example 133-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid

[0258]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid

[0259] Toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (seeEx. 2, Part F) was added to a one dram, screw-cap vial and diluted withethanol (0.5 mL). To this solution are added2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (seeEx. 12, Part B) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol)and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg,2.6 mmol/g) and the vial was tightly closed. The reaction vessel washeated in a block heater for 24-48 h at 55° C., or until TLC or MSanalysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl)and the vial resealed tightly. The solution was heated in a block heaterat 55° C. for 3-16 h, or until MS analysis indicates the completion ofthe hydrolysis. The solvents are removed with a stream of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (5N solution, 150 μl), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymass-directed HPLC to produce a white solid (24%).

[0260] MS [EI+] 584 (M+H)⁺, [EI−] 582 (M−H)⁺

Example 142-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-phenoxypropionicacid

[0261]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid

[0262] Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester (0.132mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial anddiluted with ethanol (0.5 mL). To this solution are added2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (seeEx. 12, Part B) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol)and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg,2.6 mmol/g) and the vial was tightly closed. The reaction vessel washeated in a block heater for 24-48 h at 55° C., or until TLC or MSanalysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100•1)and the vial resealed tightly. The solution was heated in a block heaterat 55° C. for 3-16 h, or until MS analysis indicates the completion ofhew hydrolysis. The solvents are removed with a stream of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (5N solution, 150•1), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bymass-directed HPLC to produce a white solid (7%). MS [EI+] 590 (M+H)⁺,[EI−] 588 (M−H)⁺

Example 153-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid

[0263]

A. 2-(4tert-Butyl-phenoxy)-propionic acid ethyl ester

[0264] 4tert-butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) wasadded dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C.under an atmosphere of nitrogen. After five min, ethyl 2-bromopropionate(6.49 mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultantmixture was allowed to stir for 18 h, gradually warming to ambienttemperature. The reaction mixture was diluted with ethyl acetate (300mL) and extracted twice with water and once with brine. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to produce acolorless oil (12.5 g, 100%) ¹H NMR (300 MHz, CDCl₃): δ 7.28 (d, 2H,J=5.5), 6.80 (d, 2H, J=5.5), 4.70 (q, 1H, J=6.6), 4.22 (q, 2H, J=7.1),1.59 (d, 3H, J=6.6), 1.28 (s, 9H), 1.25 (t, 3H, J=7.1). MS [EI+] 251(M+H)⁺, 268 (M+NH₄)⁺.

B. 2-(4tert-Butyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acidethyl ester

[0265] A solution of LDA (12.7 mL, 19.1 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solutionof 2-(4tert-butyl-phenoxy)-propionic acid ethyl ester in anhydrous THF(20 mL) also cooled to −78° C. under an atmosphere of nitrogen. Afterfive min, 4-benzyloxybenzaldehyde (3.69 g, 17.4 mmol) was added in oneportion. After stirring for 10 min, the reaction mixture was quenchedwith saturated solution of aqueous NH₄Cl (10 mL) and the mixture allowedto warm to ambient temperature. The biphasic mixture was diluted withether (100 mL) and partitioned, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (600 g silica, 25×200 mLfractions, gradient elution 0-20% ethyl acetate in hexanes) to provide acolorless oil (3.46 g, 58%) as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4-tert-butyl-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0266]3-(4-Benzyloxy-phenyl)-2-(4-tert-butyl-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester (3.46 g, 7.5 mmol) in anhydrous CH₂Cl₂ (50 mL) wascooled to 0° C. and treated with pyridine (6.0 mL, 75 mmol, d=0.978).Trifluoroacetic anhydride (2.11 mL, 15 mmol, d=1.487) was added dropwiseand the mixture was stirred for 1 h, gradually warming to ambienttemperature. The solution was washed twice with 1N HCl and the organiclayer dried over Na₂SO₄ and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4-tert-butyl-phenoxy)-3-trifluoroacetoxy-2-methylpropionicacid ethyl ester which was used without characterization.

[0267] The material was dissolved in ethyl acetate (50 mL) and treatedwith 10% palladium on carbon (1.5 g), and stirred under an atmosphere ofhydrogen for 48 h. The suspension was filtered through celite andconcentrated in vacuo to a golden oil. The residue was purified by flashcolumn chromatography (200 g silica, 30×20 mL fractions, 2% ethylacetate in CDCl₃) to provide the title compound as a colorless oil (1.06g, two steps 40%) ¹H NMR (300 MHz, CDCl₃): δ 7.21 (d, 2H, J=8.6), 7.12(d, 2H, J=8.6), 4.19 (q, 1H, J=7.1), 3.24 (d, 1H, J=12.3), 3.11 (d, 1H,J=12.3), 1.38 (s, 3H), 1.27 (s, 9H), 1.23 (t, J=7.1). MS [EI+] 357(M+H)⁺, [EI−] 355 (M−H)⁺.

C.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid:

[0268] Toluene-4-sulfonic acid2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (seeEx. 1, Part I)was added to a one dram, screw-cap vial and diluted withethanol (0.5 mL). To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) andpolystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5ene (100-125 mg, 2.6mmol/g) and the vial was tightly closed. The reaction vessel was heatedin a block heater for 24-48 h at 55° C., or until TLC or MS analysisindicates the disappearance of starting materials. The suspension wasfiltered while warm and the residue washed with ethanol (1 mL). Thesolution was treated with aqueous NaOH (5N solution, 100 μl) and thevial resealed tightly. The solution was heated in a block heater at 55°C. for 3-16 h, or until MS analysis indicates the completion of thehydrolysis. The solvents are removed with a stream of nitrogen or underreduced pressure and the residue redissolved in 1 mL water. The solutionwas acidified with aqueous HCl (5N solution, 150 μl), often causingprecipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bypreparative thin-layer silica chromatography eluting with 93:7CH₂Cl₂:methanol to produce a white solid (22%). MS [EI+] 590 (M+H)⁺,[EI−] 588 (M−H)⁺

Example 163-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid

[0269]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid

[0270] Toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (seeEx. 2, Part F) was added to a one dram, screw-cap vial and diluted withethanol (0.5 mL). To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (seeEx. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5ene(100-125 mg, 2.6 mmol/g) and the vial was tightly closed. The reactionvessel was heated in a block heater for 24-48 h at 55° C., or until TLCor MS analysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl)and the vial resealed tightly. The solution was heated in a block heaterat 55° C. for 3-16 h, or until MS analysis indicates the completion ofthe hydrolysis. The solvents are removed with a stream of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (5N solution, 150 μl), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bypreparative thin-layer silica chromatography eluting with 95:5CH₂Cl₂:MeOH to produce a white solid (45%). MS [EI+] 590 (M+H)⁺, [EI−]588 (M−H)⁺

Example 172-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid

[0271]

A.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid

[0272] Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)oxazol-4-yl)-ethyl ester(0.132mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial anddiluted with ethanol (0.5 mL). To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (seeEx. 15, Part B) and polystyrene bound1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6 mmol/g) and thevial was tightly closed. The reaction vessel was heated in a blockheater for 24-48 h at 55° C., or until TLC or MS analysis indicates thedisappearance of starting materials. The suspension was filtered whilewarm and the residue washed with ethanol (1 mL). The solution wastreated with aqueous NaOH (5N solution, 100 μl) and the vial resealedtightly. The solution was heated in a block heater at 55° C. for 3-16 h,or until MS analysis indicates the completion of the hydrolysis. Thesolvents are removed with a stream of nitrogen or under reduced pressureand the residue redissolved in 1 mL water. The solution was acidifiedwith aqueous HCl (5N solution, 150 μl), often causing precipitation ofproduct. The suspension was diluted with dichloromethane (3 mL) and theresultant biphasic solution was filtered through a Chrom-Elut column toremove water. The filtrate was concentrated in vacuo and the resultantresidue was purified by preparative thin-layer silica chromatographyeluting with 95:5 CH₂Cl₂:MeOH to produce a white solid (11%). MS [EI+]596 (M+H)⁺, [EI−] 594 (M−H)⁺

Example 182-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid

[0273]

A.2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid

[0274] Toluene-4-sulfonic acid2-(5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester(0.132mmol) (see Ex. 5, Part B) was added to a one dram, screw-cap vial anddiluted with ethanol (0.5 mL). To this solution are added3-4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethylester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15,Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene(100-125 mg, 2.6 mmol/g) and the vial was tightly closed. The reactionvessel was heated in a block heater for 24-48 h at 55° C., or until TLCor MS analysis indicates the disappearance of starting materials. Thesuspension was filtered while warm and the residue washed with ethanol(1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl)and the vial resealed tightly. The solution was heated in a block heaterat 55° C. for 3-16 h, or until MS analysis indicates the completion ofthe hydrolysis. The solvents are removed with a stream of nitrogen orunder reduced pressure and the residue redissolved in 1 mL water. Thesolution was acidified with aqueous HCl (5N solution, 150 μl), oftencausing precipitation of product. The suspension was diluted withdichloromethane (3 mL) and the resultant biphasic solution was filteredthrough a Chrom-Elut column to remove water. The filtrate wasconcentrated in vacuo and the resultant residue was purified bypreparative thin-layer silica chromatography eluting with 95:5CH₂Cl₂:MeOH to produce a white solid (10%). MS [EI+] 596 (M+H)⁺, [EI−]594 (M−H)⁺

Example 192-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid

[0275]

A.2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)propionicacid

[0276] Toluene-4-sulfonic acid2-(5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl)-ethyl ester(0.132mmol) (see Ex. 6, Part B) was added to a one dram, screw-cap vial anddiluted with ethanol (0.5 mL). To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (seeEx. 15, Part B) and polystyrene bound1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6 mmol/g) and thevial was tightly closed. The reaction vessel was heated in a blockheater for 24-48 h at 55° C., or until TLC or MS analysis indicates thedisappearance of starting materials. The suspension was filtered whilewarm and the residue washed with ethanol (1 mL). The solution wastreated with aqueous NaOH (5N solution, 100 μl) and the vial resealedtightly. The solution was heated in a block heater at 55° C. for 3-16 h,or until MS analysis indicates the completion of the hydrolysis. Thesolvents are removed with a stream of nitrogen or under reduced pressureand the residue redissolved in 1 mL water. The solution was acidifiedwith aqueous HCl (5N solution, 150 μl), often causing precipitation ofproduct. The suspension was diluted with dichloromethane (3 mL) and theresultant biphasic solution was filtered through a Chrom-Elut column toremove water. The filtrate was concentrated in vacuo and the resultantresidue was purified by preparative thin-layer silica chromatographyeluting with 95:5 CH₂Cl₂:MeOH to produce a white solid (8%). MS [EI+]596 (M+H)⁺, [EI−] 594 (M−H)⁺

Example 203-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid

[0277]

A. 2-(3-Fluorophenoxy)propionic acid ethyl ester

[0278] 3-Fluorophenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF(1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After16 h, the DMF was removed in vacuo. The residue was dissolved in ethylacetate (300 mL) and washed twice with water and once with brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to producean oil.

B. 2-(3-Fluorophenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester

[0279] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(3-fluorophenoxy)propionic acid ethyl ester (24.7 mmol) in anhydrousTHF (30 mL) also cooled to −78° C. under an atmosphere of nitrogen.After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added inone portion. After stirring for 10 min, the reaction mixture wasquenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(3-fluoro-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0280]3-(4Benzyloxyphenyl)-3-hydroxy-2-(3-fluorophenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL 9.5 mmol). The mixture was stirred for 2 h and gradually warmedto ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) was added andthe mixture was stirred vigorously. The solution was partitioned and theorganic layer was washed twice with water and brine, dried over Na₂SO₄,and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(3-fluorophenoxy)-2-methylpropionic acid ethylester as an oil.

C. 2-(3-Fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester

[0281] 2-(3-Fluorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered roughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid

[0282] A mixture of2-(3-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.87 (d, 1H, J=7.8 Hz),7.57 (d, 2H, J=7.8 Hz), 7.50-7.27 (m, 5H), 7.12 (m, 3H), 6.76 (d, 2H,J=8.6 Hz), 6.72-6.58 (m, 3H), 4.14 (t, 2H, J=6.7 Hz), 3.18 (d, 1H,J=14.1 Hz), 3.08 (d, 1H, J=14.1 Hz), 2.94 (t, 2H, J=6.7 Hz), 2.37 (s,3H), 1.38 (s, 3H). MS (ES⁺) m/z mass calcd for C₃₄H₃₁FNO₅ 552.21, found552.2.

Example 213-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid

[0283]

A.3-{4-[2-(2-Biphenylyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid

[0284] A mixture of2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol) (see Ex. 20, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, 2H, J=8.2 Hz), 7.71 (d, 2H,J=8.2 MHz), 7.63 (d, 2H, J=7.0 Hz), 7.47 (t, 2H, J=7.6 Hz), 7.41-7.38(m, 1H), 7.21-7.15 (m, 3H), 6.82 (d, 2H, J=8.6 Hz), 6.76-6.60 (m, 3H),4.22 (t, 2H, J=6.3 Hz), 3.27 (d, 1H, J=14.1 Hz), 3.13 (d, 1H, J=14.1Hz), 3.08 (t, 2H, J=6.3 Hz), 2.45 (s, 3H), 1.44 (s, 3H). MS (ES⁺) m/zexact mass calcd for C₃₄H₃₀FNO₅ 552.2186, found 552.2183.

Example 222-(3-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0285]

A.2-(3-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0286] A mixture of2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(3-fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid.¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, 2H, J=8.6 Hz), 7.70 (d, 2H,J=8.6 Hz), 7.42 (dd, 1H, J=3.5 Hz, 1.17 Hz), 7.36 (dd, 1H, J=5.1 Hz,1.17 Hz), 7.18-7.10 (m, 4H), 6.82 (d, 2H, J=8.6 Hz), 6.76-6.60 (m, 3H),4.21 (t, 2H, J=6.3 Hz), 3.26 (d, 1H, J=14.1 Hz), 3.12 (d, 1H, J=14.1Hz), 3.07 (t, 2H, J=6.3 Hz), 2.73 (s, 3H), 1.45 (s, 3H). HRMS (ES⁺) m/zexact mass calcd for C₃₂H₂₈FNO₅S 558.1750, found 558.1743.

Example 233-}4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-tert-butyl-phenoxy)-2-methyl-propionicacid

[0287]

A. 2-(3-tert-Butyl-phenoxy)-propionic acid ethyl ester

[0288] 3-tert-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) wasadded dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0°C.under an atmosphere of nitrogen. After five min, ethyl2-bromopropionate (6.49 mL, 50 mmol, d=1.394) was added rapidly dropwiseand the resultant mixture was allowed to stir for 18 h, graduallywarming to ambient temperature. The reaction mixture was diluted withethyl acetate (300 mL) and extracted twice with water and once withbrine. The organic layer was dried over Na₂SO₄ and concentrated in vacuoto produce a colorless oil.

B. 2-(3-tert-Butyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acidethyl ester

[0289] A solution of LDA (12.7 mL, 19.1 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solutionof 2-(3-tert-butyl-phenoxy)-propionic acid ethyl ester in anhydrous THF(20 mL) also cooled to −78° C. under an atmosphere of nitrogen Afterfive min, 4-benzyloxybenzaldehyde (3.69 g, 17.4 mmol) was added in oneportion. After stirring for 10 min, the reaction mixture was quenchedwith saturated solution of aqueous NH₄Cl (10 mL) and the mixture allowedto warm to ambient temperature. The biphasic mixture was diluted withether (100 mL) and partitioned, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (600 g silica, 25×200 mLfractions, gradient elution 0-20% ethyl acetate in hexanes) to provide acolorless oil (3.46 g, 58%) as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(3-tert-butyl-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0290]3-(4-Benzyloxy-phenyl)-2-(4-tert-butyl-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester (3.46 g, 7.5 mmol) in anhydrous CH₂Cl₂ (50 mL) wascooled to 0° C. and treated with pyridine (6.0 mL, 75 mmol, d=0.978).Trifluoroacetic anhydride (2.11 mL, 15 mmol, d=1.487) was added dropwiseand the mixture was stirred for 1 h, gradually warming to ambienttemperature. The solution was washed twice with 1N HCl and the organiclayer dried over Na₂SO₄ and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(3-tert-butyl-phenoxy)-3-trifluoroacetoxy-2-methylpropionicacid ethyl ester which was used without characterization.

[0291] The material was dissolved in ethyl acetate (50 mL) and treatedwith 10% palladium on carbon (1.5 g), and stirred under an atmosphere ofhydrogen for 48 h. The suspension was filtered through celite andconcentrated in vacuo to a golden oil. The residue was purified by flashcolumn chromatography (200 g silica, 30×20 mL fractions, 2% ethylacetate in CHCl₃) to provide the title compound as a colorless oil.

C.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-tert-butyl-phenoxy)-2-methyl-propionicacid

[0292] A mixture of2-(3-tert-butyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acidethyl ester (0.030 mmol) toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-tert-butyl-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 2H, J=8.21 Hz), 7.68 (d, 2H,J=8.21 Hz), 7.63 (d, 2H, J=7.04 Hz), 7.46 (t, 2H, J=7.04 Hz), 7.40-7.36(m, 1H), 7.20-7.15 (m, 3H), 7.07 (d, 1H, J=7.04 Hz), 6.90 (s, 1H), 6.83(d, 2H, J=8.60 Hz), 6.71 (dd, 1H, J=8.21 Hz, 2.74 Hz), 4.23 (t, 2H,J=6.26 Hz), 3.25 (d, 1H. J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 3.05 (t,2H, J=6.26 Hz), 2.42 (s, 3H), 1.43 (s, 3H), 1.26 (s, 9H). HRMS (ES⁺) m/zexact mass calcd for C₃₈H₄₀NO₅ 590.2906, found 590.2891.

Example 242-(3-tert-Butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0293]

A.2-(3-tert-Butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0294] A mixture of2-(3-tert-butyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acidethyl ester (0.030 mmol) (see Ex. 23, Part B), toluenesulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(3-tert-butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H, J=8.60 Hz), 7.67 (d, 2H,J=8.60 Hz), 7.36 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.33 (dd, 1H, J=3.91 Hz,1.17 Hz), 7.20-7.16 (m, 3H), 7.12-7.07 (m, 2H), 6.89 (t, 1H, J=1.96 Hz),6.84 (d, 2H, J=8.60 Hz), 6.72 (dd, 1H, J=8.60 Hz, 2.74 Hz), 4.22 (t, 2H,J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 3.01 (t,2H, J=6.65 Hz), 2.40 (s, 3H), 1.43 (s, 3H), 1.26 (s, 9H). HRMS (ES⁺) m/zexact mass calcd for C₃₆H₃₈NO₅S 596.2471, found 596.2454.

Example 252-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0295]

A. 2-(2-Fluorophenoxy)propionic acid ethyl ester

[0296] 2-Fluorophenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF(1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After16 h, the DMF was removed in vacuo. The residue was dissolved in ethylacetate (300 mL) and washed twice with water and once with brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to producean oil.

B. 2-(2-Fluorophenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester

[0297] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(2-fluorophenoxy)propionic acid ethyl ester (24.7 mmol) in anhydrousTHF (30 mL) also cooled to −78° C. under an atmosphere of nitrogen.After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added inone portion. After stirring for 10 min, the reaction mixture wasquenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(2-fluorophenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0298]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(2-fluorophenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(2-fluorophenoxy)-2-methylpropionic acid ethylester as an oil.

C. 2-(2-Fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester

[0299] 2-(2-Fluorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladiun on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0300] A mixture of2-(2-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-(4thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(2-fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 2H, J=8.60 Hz), 7.38 (d, 2H,J=3.52 Hz), 7.33 (d, 2H, J=3.52 Hz), 7.23 (d, 2H, J=8.60 Hz), 7.10 (dd,2H, J=5.08 Hz, 3.52 Hz), 7.08-7.04 (m, 1H), 7.00-6.96 (m, 2H), 6.82 (d,2H, J=8.60 Hz), 4.19 (t, 2H, J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.20(d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.65 Hz), 2.38 (s, 3H), 1.43 (s,3H). MS (ES⁺) m/z mass calcd for C₃₂H₂₈FNO₅S 558.17, number found 558.2.

Example 262-(4-Chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0301]

A. 2-(4-Chlorophenoxy)propionic acid ethyl ester

[0302] 4-Chlorophenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF(1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After16 h, the DMF was removed in vacuo. The residue was dissolved in ethylacetate (300 mL) and washed twice with water and once with brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to producean oil.

B. 2-(4-Chlorophenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester

[0303] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(4-chlorophenoxy)propionic acid ethyl ester (24.7 mmol) in anhydrousTHF (30 mL) also cooled to −78° C. under an atmosphere of nitrogen.After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added inone portion. After stirring for 10 min, the reaction mixture wasquenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4-chlorophenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0304]3-(4Benzyloxyphenyl)-3-hydroxy-2-(4chlorophenoxy)-2-methylpropionic acidethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0° C.and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed toambient temperature. Saturated aqueous Na₂CO₃ (15 mL) was added and themixture was stirred vigorously. The solution was partitioned and theorganic layer was washed twice with water and brine, dried over Na₂SO₄,and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4chlorophenoxy)-2-methylpropionic acid ethylester as an oil.

C. 2-(4-Chlorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester

[0305] 2-(4-Chlorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 1 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.2-(4-Chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0306] A mixture of2-(4chlorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)-oxazol-4-yl]ethyl ester (0.030mmol) (see Ex. 5, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(4chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 8.87 (d, 1H, J=8.21 Hz),7.69-7.67 (m, 1H ), 7.46 (d, 1H, J=8.21 Hz), 7.42 (dd, 1H, J=3.52 Hz,2.74 Hz), 7.32 (dd, 1H, J=5.08 Hz, 2.74 Hz), 7.19-7.15 (m, 3H), 7.18(dd, 2H, J=6.26 Hz, 2.74 Hz), 6.82 (dd, 4H, J=8.60 Hz, 2.74 Hz), 4.22(t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.10 (d, 1H, J=14.08 Hz),3.05 (t, 2H, J=6.26 Hz), 2.42 (s, 3H), 1.40 (s, 3H). MS (ES⁺) m/z masscalcd for C₃₂H₂₉ClNO₅S 574.15, found 574.2.

Example 273-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid

[0307]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid

[0308] A mixture of2-(4chlorophenoxy)3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol) (see Ex. 26, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4chloro-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 2H, J=8.60 Hz), 7.69 (d, 2H,J=8.21 Hz), 7.63 (d, 2H, J=6.65 Hz), 7.48-7.45 (m, 2H), 7.40 (d, 2H,J=7.04 Hz), 7.20-7.15 (m, 4H), 6.82 (d, 3H, J=8.60 Hz), 4.22 (s, 2H),3.24 (d, 1H, J=13.30 Hz), 3.13-3.07 (m, 3H), 2.43 (s, 3H), 1.25 (s, 3H).MS (ES⁺) m/z mass calcd for C₃₄H₃₁ClNO₅ 568.19, found 568.2

Example 283-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid

[0309]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid

[0310] A mixture of2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol) (see Ex. 26, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid. 1H NMR (400 MHz, CDCl₃δ 8.12 (t, 1H, J=19.94 Hz), 7.87 (td, 1H,J=19.16 Hz, 7.43 Hz), 7.61 (t, 3H, J=7.43 Hz), 7.48-7.28 (m, 4H), 7.08(t, 4H, J=6.65 Hz), 6.77 (td, 4H, J=24.63 Hz, 12.12 Hz), 4.16 (t, 2H,J=6.65 Hz), 3.18 (d, 1H, J=13.29 Hz), 3.00 (d, 1H, J=13.29 Hz), 2.90 (t,2H, J=6.65 Hz), 2.52 (d, 1H, J=15.25 Hz), 2.32 (t, 2H, J=19.55 Hz), 1.29(s, 3H) MS (ES⁺) m/z mass calcd for C₃₄H₃₁ClNO₅ 568.19, found 568.2.

Example 292-(4-Cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0311]

A. 2-(4Cyclohexylphenoxy)propionic acid ethyl ester

[0312] 4-Cyclohexylphenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), andethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrousDMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen.After 16 h, the DMF was removed in vacuo. The residue was dissolved inethyl acetate (300 mL) and washed twice with water and once with brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo toproduce an oil.

B. 2-(4-Cyclohexylphenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester

[0313] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(4-cyclohexylphenoxy)propionic acid ethyl ester (24.7 mmol) inanhydrous THF (30 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) wasadded in one portion. After stirring for 10 min, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4cyclohexylphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0314]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-cyclohexylphenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4cyclohexylphenoxy)-2-methylpropionic acidethyl ester as an oil.

C. 2-(4-Cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester

[0315] 2-(4-Cyclohexylphenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.2-(4-Cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0316] A mixture of2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol), toluene4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030mmol) (see Ex. 5, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(4cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.88 (d, 1H, J=7.82 Hz),7.64 (d, 1H, J=7.82 Hz), 7.43 (d, 1H, J=7.82 Hz), 7.41 (dd, 1H,J=3.52Hz, 1.17 Hz), 7.31 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.19 (d, 2H, J=8.60Hz), 7.10-7.06 (m, 3H), 6.84 (d, 2H, J=7.04 Hz), 6.82 (d, 2H, J=8.21Hz), 4.23 (t, 2H, J=6.65 Hz), 3.22 (d, 1H, J=14.08 Hz), 3.13 (d, 1H,J=14.08 Hz), 2.99 (t, 2H, J=6.65 Hz), 2.39 (s, 3H), 1.81 (d, 5H, J=8.60Hz), 1.40 (s, 3H), 1.38-1.32 (m, 5H). MS (ES⁺) m/z mass calcd C₃₈H₄₀NO₅S622.26, found 622.3.

Example 303-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid

[0317]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4cyclohexyl-phenoxy)-2-methyl-propionicacid

[0318] A mixture of2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (see Ex. 29, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, 2H, J=8.60 Hz), 7.66-7.62 (m,4H), 7.48-7.44 (m, 2H), 7.39-7.36 (m, 1H), 7.19 (d, 3H, J=8.60 Hz), 7.07(d, 2H, J=8.60 Hz), 6.83 (q, 3H, J=3.52 Hz), 4.13 (t, 2H, J=6.65 Hz),3.24 (d, 1H, J=13.30 Hz), 3.12 (d, 1H, J=13.30 Hz), 2.99 (t, 2H, J=66.5Hz), 2.38 (s, 3H), 1.82-1.69 (m, 4H), 1.41 (s, 3H), 1.37-1.22 (m, 6H).MS (ES⁺) m/z mass calcd for C₄₀H₄₂NO₅ 616.31, found 616.3.

Example 313-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid

[0319]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(4cyclohexyl-phenoxy)-2-methyl-propionicacid

[0320] A mixture of2-(4cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol) (see Ex. 29, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part P) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.96-7.93 (m, 1H), 7.64(t, 3H, J=8.21 Hz), 7.50-7.43 (m, 3H), 7.37 (d, 1H, J=8.21 Hz), 7.18 (d,2H, J=8.60 Hz), 7.07 (d, 2H, J=8.60 Hz), 6.83 (dd, 4H, J=8.60 Hz, 5.47Hz), 4.22 (t, 2H, J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.16 (d, 1H,J=14.08 Hz), 2.99 (t, 2H, J=6.65 Hz), 2.39 (s, 3H), 2.17 (s, 1H), 1.81(d, 4H, J=9.78 Hz), 1.41 (s, 3H), 1.37-1.22 (m, 5H). MS (ES⁺) m/z masscalcd for C₄₀H₄₂NO₅ 616.31, found 616.3.

Example 322-(3,4-Dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0321]

A. 2-(3,4-Dimethylphenoxy)propionic acid ethyl ester

[0322] 3,4-Dimethylphenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), andethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrousDMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen.After 16 h, the DMF was removed in vacuo. The residue was dissolved inethyl acetate (300 mL) and washed twice with water and once with brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo toproduce an oil.

B.3-(4-Benzyloxyphenyl)-2-(3,4-dimethylphenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester

[0323] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(3,4-dimethylphenoxy)propionic acid ethyl ester (24.7 mmol) inanhydrous THF (30 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) wasadded in one portion. After stirring for 10 min, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warn to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(3,4-dimethylphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0324]3-(4Benzyloxyphenyl)-3-hydroxy-2-(3,4-dimethylphenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) and pyridine(9.5 mmol) was cooled to 0° C. and treated with trifluoroaceticanhydride (19 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. An aqueous solution of 1N HCl (25 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(3,4-dimethylphenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester as an oil.

C. 2-(3,4-Dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester

[0325]3-(4-Benzyloxyphenyl)-2-(3,4-dimethylphenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.2-(3,4-Dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxyγ-phenyl)-propionicacid

[0326] A mixture of2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(3,4-dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.16-8.07 (m, 2H), 7.74-7.71 (m, 2H),7.44-7.35 (m, 2H), 7.18 (d, 2H, J=8.8 Hz), 7.14-7.11 (m, 1H), 7.00 (d,1H, J=8.4 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.70 (d, 1H, J=2.6 Hz), 6.64 (dd,1H, J=8.4, 2.6 Hz), 4.31-4.26 (m, 2H), 3.21 and 3.11 (d of Abq, 2H,J=14.0 Hz), 3.12-3.08 (m, 2H), 2.44 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H),1.39 (s, 3H). IR (KBr) 3480, 3000, 1716, 1610, 1512, 1250, 1119 cm⁻¹.HRMS (ES⁺) m/z exact mass calcd for C₃₄H₃₄NO₅S 568.2158, found 568.2168.

Example 333-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid

[0327]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid

[0328] A mixture of2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (Ex. 32, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid ¹H NMR (400 MHz, CDCl₃) δ 8.23-8.21 (m, 1H), 7.95 (d, 1H, J=7.6Hz), 7.67-7.62(m, 3H), 7.50-7.42 (m, 3H), 7.38-7.34 (m, 1H), 7.19 (d,2H, J=8.8 Hz), 6.95 (d, 1H, J=8.2 Hz), 6.82 (d, 2H, J=8.8 Hz), 6.71 (d,1H, J=2.8 Hz), 6.63 (dd, 1H, J=8.2, 2.8 Hz), 4.20 (t, 2H, J=6.4 Hz),3.24 and 3.13 (d of Abq, 2H, J=14.0 Hz), 3.01 (t, 2H, J=6.4 Hz), 2.39(s, 3H), 2.16 (s, 6H, 1.38 (s, 3H). IR (KBr) 3480, 2980, 1717, 1611,1512, 1248, 1118 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd for C₃₆H₃₆NO₅562.2593, found 562.2598.

Example 343-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid

[0329]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid

[0330] A mixture of2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (see Ex. 32, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, 2H, J=8.4 Hz), 7.71 (d, 2H,J=8.4 Hz), 7.65-7.62 (m, 2H), 7.49-7.45 (m, 2H), 7.42-7.30 (m, 1H), 7.19(d, 2H, J=8.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.70(d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4, 2.4 Hz), 4.26 (t, 2H, J=6.0 Hz),3.22 and 3.11 (d of Abq, 2H, J=14.0 Hz), 3.09 (t, 2H, J=6.0 Hz), 2.44(s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3480, 2950,1718, 1611, 1512, 1248, 1177cm⁻¹. HRMS (ES⁺) m/z exact mass calcd forC₃₆H₃₆NO₅ 562.2593, found 562.2595.

Example 352-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy-propionicacid

[0331]

A. 2-(p-Tolyloxy)propionic acid ethyl ester

[0332] p-Hydroxytoluene (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), andethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrousDMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen.After 16 h, the DMF was removed in vacuo. The residue was dissolved inethyl acetate (300 mL) and washed twice with water and once with brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo toproduce an oil.

B. 2-(p-Tolyloxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethylester

[0333] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(p-tolylyoxy)propionic acid ethyl ester (24.7 mmol) in anhydrous THF(30 mL) also cooled to −78° C. under an atmosphere of nitrogen. After 5min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added in oneportion. After stirring for 10 min, the reaction mixture was quenchedwith saturated solution of aqueous NH₄Cl (10 mL) and the mixture allowedto warm to ambient temperature. The biphasic mixture was diluted withether (100 mL) and partitioned, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (600 g silica, 25×200 mLfractions, gradient elution 0-20% ethyl acetate in hexanes) to providean oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(p-tolyloxy)-3-hydroxy-2-methylpropionic acidethyl ester which was used without further characterization orpurification.

[0334] 3-(4-Benzyloxyphenyl)-3-hydroxy-2-(p-tolyloxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce2-(p-tolyloxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl esteras an oil.

C. 2-(p-Tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester

[0335] 2-(p-Tolyloxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethylester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with5% palladium on carbon (300 mg), and stirred under an atmosphere ofhydrogen for 20 h. The suspension was filtered through celite andconcentrated in vacuo to an oil.

D.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy-propionicacid

[0336] A mixture 2-(p-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-2-p-tolyloxy-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, 2H, J=8.4 Hz), 7.71 (d, 2H,J=8.4 Hz), 7.42 (dd, 1H, J=3.8, 1.0 Hz), 7.36 (dd, 1H, J=5.0, 1.0 Hz),7.26-7.25 (m, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.12 (dd, 1H, J=5.0, 3.8 Hz),7.05 (d, 2H, J=8.4 Hz), 6.81 and 6.81 (d of Abq, 4H, J=8.8 Hz), 4.23 (t,2H, J=6.2 Hz), 3.23 and 3.12 (d of Abq, 2H, J=14.0 Hz), 3.07 (t, 2H,J=6.2 Hz), 2.43 (s, 3H), 2.28 (s, 3H), 1.39 (s, 3H). IR (KBr) 3450,1718, 1681, 1509, 1216 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd forC₃₃H₃₂NO₅S 554.2001, found 554.2015.

Example 363-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid

[0337]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid

[0338] A mixture 2-(p-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester (0.030 mmol) (see Ex. 35, Part C), toluene-4-sulfonicacid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol)(see Ex. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol(2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL)and additional ethanol (1 mL) was added to the reaction mixture and itwas heated at reflux for an additional 2 h. The reaction was cooled andthe solvent removed in vacuo. The residue was acidified with aqueous 1 NHCl (5 mL), extracted with water and CH₂Cl₂ and the organic layer driedby passing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.87 (bs, 1H), 8.07 (d, 2H, J=8.6 Hz),7.72 (d, 2H, J=8.6 Hz), 7.65-7.63 (m, 2H), 7.50-7.38 (m, 3H), 7.19 (d,2H, J=8.4 Hz), 7.04 (d, 2H, J=8.0 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.80 (d,2H, J=8.0 Hz), 4.23 (t, 2H, J=6.0 Hz), 3.24 and 3.22 (d of Abq, 2H,J=14.0 Hz), 3.09 (t, 2H, J=6.0 Hz), 2.45 (s, 3H), 2.28 (s, 3H), 1.38 (s,3H). IR (KBr) 3450, 2924, 1719, 1682, 1509, 1207 cm⁻¹. HRMS (ES⁺) m/zexact mass calcd for C₃₅H₃₄NO₅ 548.2437, found 548.2455.

Example 373-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid

[0339]

A. 2-(4-Trifluoromethoxyphenoxy)propionic acid ethyl ester

[0340] 4-Trifluoromethoxyphenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol),and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined inanhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere ofnitrogen. After 16 h, the DMF was removed in vacuo. The residue wasdissolved in ethyl acetate (300 mL) and washed twice with water and oncewith brine. The organic layer was dried over Na₂SO₄ and concentrated invacuo to produce an oil.

B. 2-(4Trifluoromethoxyphenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionicacid ethyl ester

[0341] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(4-trifluoromethoxyphenoxy)propionic acid ethyl ester (24.7 mmol) inanhydrous THF (30 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) wasadded in one portion. After stirring for 10 min, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warn to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4-trifluoromethoxyphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0342]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-trifluoromethoxyphenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4-trifluoromethoxyphenoxy)-2-methylpropionicacid ethyl ester as an oil.

C. 2-(4-Trifluoromethoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester

[0343]2-(4-Trifluoromethoxyphenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid

[0344] A mixture of2-(4-trifluoromethoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 2H, J=8.4 Hz), 7.68 (d, 2H,J=8.4 Hz), 7.63 (d, 2H, J=8.4 Hz), 7.49-7.43 (m, 2H), 7.41-7.37 (m, 1H),7.18 (d, 2H, J=8.4 Hz), 7.09 (d, 2H, J=8.4 Hz), 6.90 (d, 2H, J=8.6 Hz),6.83 (d, 2H, J=8.6 Hz), 4.22 (t, 2H, J=6.4 Hz), 3.25 and 3.14 (d of Abq,2H, J=14.0 Hz), 3.05 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 1.43 (s, 3H). IR(KBr) 3600, 3000, 1717, 1612, 1504, 1265 cm⁻¹. HRMS (ES⁺) m/z exact masscalcd for C₃₅H₃₁NO₆F₃ 618.2103, found 618.2104.

Example 383-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid

[0345]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid

[0346] A mixture of2-(4-trifluoromethoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl (0.030 mmol) (see Ex. 37, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 11.80 (bs, 1H), 8.25 (bs, 1H), 7.98-7.94(m, 1H), 7.70-7.64 (m, 3H), 7.53-7.43 (m, 3H), 7.39-7.35 (m, 1H), 7.18(d, 2H, J=8.8 Hz), 7.06 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 6.83(d, 2H, J=8.8 Hz), 4.22 (t, 2H, J=6.6 Hz), 3.24 and 3.14 (d of ABq, 2H,J=14.2 Hz), 3.05 (t, 2H, J=6.6 Hz), 2.42 (s, 3H), 1.42 (s, 3H). IR (KBr)3600, 3100, 1716, 1612, 1504, 1265 cm⁻¹. HRMS (ES⁺) m/z exact mass calcdfor C₃₅H₃₁NO₆F₃ 618.2103, found 618.2108.

Example 392-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid

[0347]

A.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid

[0348] A mixture of2-(4-trifluoromethoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl (0.030 mmol) (see Ex. 37, Part C), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL.) was added to the reactionmixture and it was heated at reflux for an additional 2 h. The reactionwas cooled and the solvent removed in vacuo. The residue was acidifiedwith aqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and theorganic layer dried by passing it through a Varian Chem Elut 1003cartridge. The solvent was removed in vacuo to give2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 2H, J=8.4 Hz), 7.66 (d, 2H,J=8.4 Hz), 7.39 (dd, 1H, J=3.6, 1.2 Hz), 7.33 (dd, 1H, J=5.2, 1.2 Hz),7.18 (d, 2H, J==8.4 Hz), 7.12-7.07 (m, 3H), 6.92-6.88 (m, 2H), 6.83 (d,2H, J=8.4 Hz), 4.20 (t, 2H, J=6.4 Hz), 3.25 and 3.14 (d of ABq, 2H,J=14.0 Hz), 3.00 (t, 2H, J=6.4 Hz), 2.40 (s, 3H), 1.43 (s, 3H). IR (KBr)3600, 3000, 1718, 1504, 1265 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd forC₃₃H₂₉NO₆F₃S 624.1667, found 624.1675.

Example 402-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid

[0349]

A. 2-Phenoxybutyric acid ethyl ester

[0350] Phenol (28.5 g, 0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromobutyrate (0.30 mol) were combined in anhydrous DMF (1000 mL) andstirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMFwas removed in vacuo. The residue was dissolved in ethyl acetate (300mL) and washed twice with water and once with brine. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to produce an oil.

[0351] B. 2-(4-Benzyloxybenzyl)-2-phenoxybutric acid ethyl ester

[0352] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solutionof 2-phenoxybutyric acid ethyl ester (24.7 mmol) in anhydrous THF (30mL) also cooled to −78° C. under an atmosphere of nitrogen. After 5 min,4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added in one portion.After stirring for 10 min, the reaction mixture was quenched withsaturated solution of aqueous NH₄Cl (10 mL) and the mixture allowed towarm to ambient temperature. The biphasic mixture was diluted with ether(100 mL) and partitioned, and the organic layer was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified byflash column chromatography (600 g silica, 25×200 mL fractions, gradientelution 0-20% ethyl acetate in hexanes) to provide an oil as a mixtureof inseparable diastereomers of2-[(4-benzyloxyphenyl)hydroxymethyl]-2-phenoxy-butyric acid ethyl esterwhich was used without further characterization or purification.

[0353] 2-[(4-Benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-butyric acidethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0° C.and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane (1.51mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed toambient temperature. Saturated aqueous Na₂CO₃ (15 mL) was added and themixture was stirred vigorously. The solution was partitioned and theorganic layer was washed twice with water and brine, dried over Na₂SO₄,and concentrated in vacuo to produce2-(4-benzyloxybenzyl)-2-phenoxybutyric acid ethyl ester as an oil.

C. 2-(4-Hydroxybenzyl)-2-phenoxybutyric acid ethyl ester

[0354] 2-(4-Benzyloxybenzyl)-2-phenoxybutyric acid ethyl ester (2.1mmol) was dissolved in ethyl acetate (30 mL) and treated with 5%palladium on carbon (300 mg), and stirred under an atmosphere ofhydrogen for 20 h. The suspension was filtered through celite andconcentrated in vacuo to an oil.

D.2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyric-acid

[0355] A mixture of 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part 1) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid. ¹H NMR (400 MHz, CDCl₃) δ 8.05-8.03 (m, 2H), 7.68-7.61 (m, 4H),7.48-7.44 (m, 2H), 7.40-7.35 (m, 1H), 7.32-7.25 (m, 2H), 7.09-6.96 (m,5H), 6.79-6.70 (m, 2H), 4.19 (t, 2H, J=6.4 Hz), 3.29 (s, 2H), 2.99 (t,2H, J=6.4 Hz), 2.39 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd,1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).

Example 412-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid

[0356]

A.2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid

[0357] A mixture of 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethylester (0.030 mmol) (see Ex. 40, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.20 (m, 1H), 7.96-7.93 (m, 1H),7.68-7.63 (m, 3H), 7.53-7.43 (m, 3H), 7.39-7.34 (m, 1H), 7.32-7.24 (m,2H), 7.09-7.05 (m, 1H), 7.02-6.97 (m, 4H), 6.78-6.73 (m, 2H), 4.20 (t,2H, J=6.4 Hz), 3.29 (s, 2H), 3.01 (t, 2H, J=6.4 Hz), 2.39 (s, 3H), 2.14(qd, 1H, J=14.8, 7.6 Hz), 2.08 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H,J=7.6 Hz.

Example 422-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid

[0358]

A.2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid

[0359] A mixture of 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethylester (0.030 mmol) (see Ex. 40, Part C), toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030mmol) (see Ex. 5, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid. ¹H NMR (400 MHz, CDCl₃) δ 8.22-8.21 (m, 1H), 7.89-7.85 (m, 1H),7.66-7.62 (m, 1H), 7.45-7.40 (m, 2H), 7.32-7.25 (m, 3H), 7.11-6.97 (m,6H), 6.77 (d, 2H, J=8.4 Hz), 4.20 (t, 2H, J=6.4 Hz), 3.29 (s, 2H), 2.98(t, 2H, J=6.4 Hz), 2.39 (s, 3H), 2.14 (qd, 1H, J=14.6, 7.6 Hz), 2.07(qd, 1H, J=14.6, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).

Example 433-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

[0360]

A. 2-(4Trifluoromethylphenoxy)propionic acid ethyl ester

[0361] 4-Trifluoromethylphenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol),and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined inanhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere ofnitrogen. After 16 h, the DMF was removed in vacuo. The residue wasdissolved in ethyl acetate (300 mL) and washed twice with water and oncewith brine. The organic layer was dried over Na₂SO₄ and concentrated invacuo to produce an oil.

B. 2-(4-Trifluoromethylphenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionicacid ethyl ester

[0362] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry is ice/acetone bath and then added to asolution 2-(4-trifluoromethylphenoxy)propionic acid ethyl ester (24.7mmol) in anhydrous THF (30 mL) also cooled to −78° C. under anatmosphere of nitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g,22.4 mmol) was added in one portion. After stirring for 10 min, thereaction mixture was quenched with saturated solution of aqueous NH₄Cl(10 mL) and the mixture allowed to warm to ambient temperature. Thebiphasic mixture was diluted with ether (100 mL) and partitioned, andthe organic layer was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (600 g silica, 25×200 mL fractions, gradient elution0-20% ethyl acetate in hexanes) to provide an oil as a mixture ofinseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4-trifluoromethylphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0363]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-trifluoromethylphenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4-trifluoromethylphenoxy)-2-methylpropionicacid ethyl ester as an oil.

C. 2-(4-Trifluoromethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester

[0364]2-(4-Trifluoromethylphenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

[0365] A mixture of2-(4-trifluoromethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, 2H, J=8.4 Hz), 7.67-7.60 (m,4H), 7.52-7.44 (m, 4H), 7.42-7.36 (m, 1H), 7.18 (d, 2H, J=8.4 Hz), 6.96(d, 2H, J=8.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.18 (t, 2H, J=6.2 Hz), 3.89(bs, 1H), 3.27 and 3.19 (d of ABq, 2H, J=13.8 Hz), 3.03 (t, 2H, J=6.2Hz), 2.41 (s, 3H), 1.50 (s, 3H). IR (KBr) 3420, 2950, 1721, 1613, 1513,1327 1248 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd for C₃₅H₃₁NO₅F₃602.2154, found 602.2151.

Example 442-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionicacid

[0366]

A.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid

[0367] A mixture of2-(4-trifluoromethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl (0.030 mmol) (see Ex. 43, Part C), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.96-7.92 (m, 1H),7.68-7.61 (m, 3H), 7.51-7.43 (m, 4H), 7.19-7.15 (m, 2H), 6.93 (d, 2H,J=8.4 Hz), 6.82 (d, 2H, J=8.4 Hz), 4.20 (t, 2H, J=6.4 Hz), 3.26 and 3.18(d of ABq, 2H, J=14.0 Hz), 3.05 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 1.49(s, 3H).

Example 453-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid

[0368]

A. 2-(3,4-Difluorophenoxy)propionic acid ethyl ester

[0369] 3,4-Difluorophenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), andethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrousDMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen.After 16 h, the DMF was removed in vacuo. The residue was dissolved inethyl acetate (300 mL) and washed twice with water and once with brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo toproduce an oil.

B. 2-(3,4-Difluorophenoxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acidethyl ester

[0370] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(3,4-difluorophenoxy)propionic acid ethyl ester (24.7 mmol) inanhydrous THF (30 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) wasadded in one portion. After stirring for 10 min, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(3,4-difluoro-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0371]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(3,4difluoro-phenoxy)-2-methylpropionicacid ethyl ester (9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0°C. and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane(1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. Saturated aqueous Na₂CO₃ (15 mL) wasadded and the mixture was stared vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(3,4difluorophenoxy)-2-methylpropionic acidethyl ester as an oil.

C. 2-(3,4-Difluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester

[0372] 2-(3,4-Difluorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)2-methyl-propionicacid

[0373] A mixture of2-(3,4-difluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4difluoro-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 2H, J=8.4 Hz), 7.36 (d, 2H,J=8.4 Hz), 7.63 (dd, 2H, J=7.6, 1.2 Hz), 7.49-7.45 (m, 2H), 7.41-7.37(m, 1H), 7.18 (d, 2H, J=8.8 Hz), 7.00 (q, 1H, J=9.5 Hz), 6.84 (d, 2H,J=8.8 Hz), 6.76 (ddd, 1H, J=11.2, 6.4, 2.8 Hz), 6.64-6.59 (m, 1H), 4.22(t, 2H, J=6.2 Hz), 3.23 and 3.11 (d of ABq, 2H, J=14.0 Hz), 3.07 (t, 2H,J=6.2 Hz), 2.44 (s, 3H), 1.39 (s, 3H).

Example 463-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid

[0374]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid

[0375] A mixture of2-(3,4-difluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (see Ex. 45, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.23 (bs, 1H), 7.94 (d,1H, J=8.0 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.65 (d, 2H, J=7.6 Hz), 7.53 (t,1H, J=7.6 Hz), 7.48-7.43 (m, 2H), 7.40-7.35 (m, 1H), 7.17 (d, 2H, J=8.4Hz), 6.97 (q, 1H, J=9.6 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (ddd, 1H,J=12.0, 7.2, 3.2 Hz), 6.62-6.58 (m, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.23and 3.10 ( d of ABq, 2H, J=14.0 Hz), 3.08 (t, 2H, J=6.4 Hz), 2.44 (s,3H), 1.37 (s, 3H).

Example 472-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0376]

A.2-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0377] A mixture of2-(3,4difluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (see Ex. 45, Part C), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(3,4-difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, 2H, J=8.8 Hz), 7.98 (bs, 1H),7.67 (d, 2H, J=8.8 Hz), 7.42 (dd, 1H, J=4.0, 1.0 Hz), 7.36 (d, 1H, J=4.8Hz), 7.17 (d, 2H, J=8.8 Hz), 7.12 (dd, 1H, J=4.8, 4.0 Hz), 7.00 (q, 1H,J=9.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.76 (ddd, 1H, J=11.6, 6.8, 3.2 Hz),6.63-6.59 (m, 1H), 4.21 (t, 2H, J=6.6 Hz), 3.23 and 3.10 (d of ABq, 2H,J=14.2 Hz), 3.07 (t, 2H, J=6.6 Hz), 2.43 (s, 3H), 1.38 (s, 3H).

Example 483-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid

[0378]

A. 2-(m-Tolyloxy)propionic acid ethyl ester

[0379] m-Hydroxytoluene (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), andethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrousDMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen.After 16 h, the DMF was removed in vacuo. The residue was dissolved inethyl acetate (300 mL) and washed twice with water and once with brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo toproduce an oil.

B.3-(4-Benzyloxyphenyl)-2-methyl-2-m-tolyloxy-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester

[0380] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(m-tolylyoxy)propionic acid ethyl ester (24.7 mmol) in anhydrous THF(30 mL) also cooled to −78° C. under an atmosphere of nitrogen. After 5min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added in oneportion. After stirring for 10 min, the reaction mixture was quenchedwith saturated solution of aqueous NH₄Cl (10 mL) and the mixture allowedto warm to ambient temperature. The biphasic mixture was diluted withether (100 mL) and partitioned, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (600 g silica, 25×200 mLfractions, gradient elution 0-20% ethyl acetate in hexanes) to providean oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(m-tolyloxy)-3-hydroxy-2-methylpropionic acidethyl ester which was used without further characterization orpurification.

[0381] 3-(4-Benzyloxyphenyl)-3-hydroxy-2-(m-tolyloxy)-2-methylpropionicacid ethyl ester (13.4 mmol) in anhydrous CH₂Cl₂ (100 mL) and pyridine(134 mmol) was cooled to 0° C. and treated with trifluoroaceticanhydride (26.9 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. An aqueous solution of 1N HCl (160 mL)was added and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)2-methyl-2-m-tolyloxy-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester as an oil.

C. 2-(m-Tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester

[0382]3-(4-Benzyloxyphenyl)-2-methyl-2-m-tolyloxy-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid

[0383] A mixture of2-(m-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester(0.095 g, 0.030 mmol), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) and 325mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to refluxfor 24 h under N₂. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1mL) was added to the reaction mixture and it was heated at reflux for anadditional 2 h. The reaction was cooled and the solvent removed invacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extractedwith water and CH₂Cl₂ and the organic layer dried by passing it througha Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo togive3-(4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.17 (m, 1H), 7.92 (d, 1H, J=7.04Hz), 7.61-7.57 (m, 3H), 7.45-7.36 (m, 3H), 7.31-7.28 (m, 1H), 7.11 (d,2H, J=8.60 Hz), 7.05 (t, 1H, J=7.82 Hz), 6.82-6.75(m, 3H), 6.65-6.61 (m,2H), 4.17 (t, 2H, J=6.65 Hz), 3.17 (d, 1H, J=13.69 Hz), 3.06 (d, 1H,J=13.69 Hz), 2.96 (t, 2H, J=6.65 Hz) 2.33 (s, 3H), 2.21 (s, 3H), 1.35(s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₃₅H₃₄NO₅ 548.2437, found548.2415.

Example 493-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid

[0384]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid

[0385] A mixture of2-(m-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester(0.095 g, 0.030 mmol) (see Ex. 48, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) and 325mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to refluxfor 24 h under N₂. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1mL) was added to the reaction mixture and it was heated at reflux for anadditional 2 h. The reaction was cooled and the solvent removed invacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extractedwith water and CH₂Cl₂ and the organic layer dried by passing it througha Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo togive3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, 2H, J=8.21 Hz), 7.70 (d, 2H,J=8.60 Hz), 7.64-7.62 (m, 2H), 7.48-7.45 (m, 2H), 7.41-7.37 (m, 1H),7.18 (d, 2H, J=8.60 Hz), 7.12 (t, 1H, J=7.82 Hz), 6.86-6.81 (m, 3H),6.72-6.68 (m, 2H), 4.22 (t, 2H, J=5.86 Hz), 3.24 (d, 1H, J=14.08 Hz),3.13 (d, 1H, J=14.08 Hz), 3.08 (t, 2H, J=5.86 Hz) 2.44 (s, 3H), 2.28 (s,3H), 1.42 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₃₅H₃₄NO₅548.2437, found 548.2459.

Example 502-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-m-tolyloxy-propionicacid

[0386]

A.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-m-tolyloxy-propionicacid

[0387] A mixture of2-(m-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester(0.095 g, 0.030 mmol) (see Ex. 48, Part C), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-m-tolyloxy-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H, J=8.60 Hz), 7.68 (d, 2H,J=8.60 Hz), 7.40 (d, 1H, J=3.52 Hz), 7.34 (d, 1H, J=4.69 Hz), 7.18 (d,2H, J=8.21 Hz), 7.15-7.09 (m, 2H), 6.87-6.82 (m, 3H), 6.72-6.69 (m, 2H),4.22 (t, 2H, J=6.26 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08Hz), 3.03 (t, 2H, J=6.26 Hz) 2.41 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H);HRMS (ES⁺) m/z exact mass calcd for C₃₃H₃₂NO₅S 554.2001, found 554.2022.

Example 513-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid

[0388]

A. 2-4-Fluorophenoxy)propionic acid ethyl ester

[0389] 4-Fluorophenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF(1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After16 h, the DMF was removed in vacuo. The residue was dissolved in ethylacetate (300 mL) and washed twice with water and once with brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to producean oil.

B.3-(4-Benzyloxyphenyl)-2-(4-fluoro-phenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester

[0390] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(4-fluoro-phenoxy)propionic acid ethyl ester (24.7 mmol) in anhydrousTHF (30 mL) also cooled to −78° C. under an atmosphere of nitrogen.After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added inone portion. After stirring for 10 min. the reaction mixture wasquenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4-fluorophenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0391]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-fluorophenoxy)-2-methylpropionicacid ethyl ester (13.4 mmol) in anhydrous CH₂Cl₂ (100 mL) and pyridine(134 mmol) was cooled to 0° C. and treated with trifluoroaceticanhydride (26.9 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. An aqueous solution of 1N HCl (150 mL)was added and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4-fluorophenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester as an oil.

C. 2-(4-Fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester

[0392]3-(4-Benzyloxyphenyl)-2-(4-fluoro-phenoxy)2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid

[0393] A mixture of2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0,60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid ¹H NMR (400 MHz, CDCl₃) δ 8.21-8.20 (m, 1H), 7.94-7.92 (m, 1H),7.65-7.62 (m, 2H), 7.50-7.34 (m, 4H), 7.17 (d, 2H, J=8.60 Hz), 6.93-6.77(m, 7H), 4.21 (t, 2H, J=6.65 Hz), 3.20 (d, 1H, J=14.00 Hz), 3.13 (d, 1H,J=14.00 Hz), 3.01 (t, 2H, J=6.65 Hz) 2.40 (s, 3H), 1.37 (s, 3H); HRMS(ES⁺) m/z exact mass calcd for C₃₄H₃₁NO₅F 552.2186, found 552.2175.

Example 523-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid

[0394]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4fluoro-phenoxy)-2-methyl-propionicacid

[0395] A mixture of2-(4-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol) (see Ex. 51, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to3-{4-[2-(2-biphenyl-4yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, 2H, J=6.65 Hz), 7.68 (d, 2H,J=6.65 Hz), 7.64 (d, 2H, J=7.04 Hz), 7.48-7.38 (m, 3H, 7.19 (d,) 2H,J=8.99 Hz), 6.94-6.82 (m, 6H), 4.22 (t, 2H, J=6.65 Hz), 3.23 (d, 1H,J=14.08 Hz), 3.12 (d, 1H, J=14.08 Hz), 3.05 (t, 2H, J=6.65 Hz) 2.42 (s,3H), 1.37 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₃₄H₃₁NO₅F552.2186, found 552.2202

Example 532-(4-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0396]

A.2-(4-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0397] A mixture of2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester (0.030 mmol) (see Ex. 51, Part C), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to2-(4-fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H, J=8.60 Hz), 7.67 (d, 2H,J=8.60 Hz), 7.40 (dd, 1H, J=5.52 Hz, J=1.17 Hz), 7.33 (dd, 1H, J=5.08Hz, J=1.17 Hz), 7.18 (d, 2H, J=8.99 Hz), 7.12-7.09 (m, 1H), 7.11 (dd,1H, J=5.08 Hz, J=3.52 Hz), 6.95-6.82 (m, 5H), 4.21 (t, 2H, J=6.26 Hz),3.22 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 3.03 (t, 2H, J=6.26Hz) 2.41 (s, 3H), 1.37 (s, 3H); HRMS (ES⁺) m/z exact mass calcd forC₃₂H₂₉NO₅FS 558.1750, found 558.1769

Example 542-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid

[0398]

A. 2-(3-Trifluoromethylphenoxy)propionic acid ethyl ester

[0399] 3-Trifluoromethylphenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol),and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined inanhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere ofnitrogen. After 16 h, the DMF was removed in vacuo. The residue wasdissolved in ethyl acetate (300 mL) and washed twice with water and oncewith brine. The organic layer was dried over Na₂SO₄ and concentrated invacuo to produce an oil.

B.3-(4-Benzyloxyphenyl)-2-methyl-3-(2,2,2-trifluoroacetoxy)-2-(3-trifluoromethylphenoxy)-propionicacid ethyl ester

[0400] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(3-trifluoromethylphenoxy)propionic acid ethyl ester (24.7 mmol) inanhydrous THF (30 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) wasadded in one portion. After stirring for 10 min, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(3-trifluoromethylphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0401]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(3-trifluoromethylphenoxy)-2-methylpropionicacid ethyl ester (13.4 mmol) in anhydrous CH₂Cl₂ (100 mL) and pyridine(134 mmol) was cooled to 0° C. and treated with trifluoroaceticanhydride (26.9 mmole). The mixture was stirred for 2 h and graduallywarned to ambient temperature. An aqueous solution of 1N HCl (150 mL)was added and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-methyl-3-(2,2,2-trifluoroacetoxy)-2-(3-trifluoromethylphenoxy)-propionicacid ethyl ester as an oil.

C. 2-(3-Trifluoromethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester

[0402]3-(4-Benzyloxyphenyl)-2-methyl-3-(2,2,2-trifluoroacetoxy)-2-(3-trifluoromethylphenoxy)-propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid

[0403] A mixture of2-(3-trifluoromethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, 2H, J=8.60 Hz), 7.69 (d, 2H,J=8.60 Hz), 7.41 (dd, 1H, J=3.52 Hz, J=1.17 Hz), 7.36-7.32 (m, 2H), 7.15(d, 2H, J=8.60 Hz), 7.16-7.10 (m, 3H), 7.05-7.02 (m, 1H), 6.82 (d, 2H,J=8.60 Hz), 4.21 (t, 2H, J=6.26 Hz), 3.27 (d, 1H, J=14.08 Hz), 3.16 (d,1H, J=14.08 Hz), 3.02 (t, 2H, J=6.26 Hz), 2.43 (s, 3H), 1.46 (s, 3H);HRMS (ES⁺) m/z exact mass calcd for C₃₃H₂₉NO₅F₃S 608.1718, found 608.

Example 553-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid

[0404]

A. 2-(3-Methoxyphenoxy)propionic acid ethyl ester

[0405] 3-Methoxyphenol (0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF(1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After16 h, the DMF was removed in vacuo. The residue was dissolved in ethylacetate (300 mL) and washed twice with water and once with brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to producean oil.

B.3-(4Benzyloxy)-2-(3-methoxyphenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester

[0406] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(3-methoxyphenoxy)propionic acid ethyl ester (24.7 mmol) in anhydrousTHF (30 mL) also cooled to −78° C. under an atmosphere of nitrogen.After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added inone portion. After stirring for 10 min, the reaction mixture wasquenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-3-methoxyphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0407]3-(4-Benzyloxyphenyl)-3-hydroxy-2-(3-methoxyphenoxy)-2-methylpropionicacid ethyl ester (13.4 mmol) in anhydrous CH₂Cl₂ (100 mL) and pyridine(134 mmol) was cooled to 0° C. and treated with trifluoroaceticanhydride (26.9 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. An aqueous solution of 1N HCl (150 mL)was added and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxy)-2-(3-methoxyphenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester as an oil.

C. 2-(3-Methoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester

[0408]3-(4-Benzyloxy)-2-(3-methoxyphenoxy)-2-methyl-3-2,2,2-trifluoroacetoxy)propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid

[0409] A mixture of2-(3-methoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl(0.030 mmol), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (t, 1H, J=1.76 Hz), 7.97-7.94 (m,1H), 7.77-7.75 (m, 1H), 7.65-7.64 (m, 2H), 7.56 (t, 1H, J=7.82 Hz),7.48-7.44 (m, 2H), 7.41-7.39 (m, 1H), 7.17-7.12 (m, 3H), 6.81 (d, 2H,J=8.60 Hz), 6.61-6.58 (m, 1H), 6.49-6.46 (m, 1H), 6.45 (t, 1H, J=2.35Hz), 4.23 (t, 2H, J=5.86 Hz), 3.74 (s, 3H), 3.24 (d, 1H, J=14.08 Hz),3.13-3.10 (m, 3H), 2.46 (s, 3H), 1.43 (s, 3H); HRMS (ES⁺) m/z exact masscalcd for C₃₅H₃₄NO₆ 564.2386, found 564.2375

Example 563-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid

[0410]

A.3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid

[0411] A mixture of2-(3-methoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl(0.030 mmol) (see Ex. 55, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid. ¹H NMR (400 M&, CDCl₃) δ 8.06 (d, 2H, J=8.21 Hz), 7.71-7.67 (m,3H), 7.65-7.62 (m, 2H), 7.48-7.44 (m, 2H), 7.41-7.37 (m, 1H), 7.18-7.12(m, 2H), 6.82 (d, 2H, J=8.60 Hz), 6.61-6.45 (m, 3H), 4.22 (t, 2H, J=6.25Hz), 3.74 (s, 3H), 3.25 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz),3.07 (t, 2H, J=6.25 Hz) 2.43 (s, 3H), 1.44 (s, 3H); HRMS (ES⁺) m/z exactmass calcd for C₃₅H₃₄NO₆ 564.2386, found 564.2388

Example 572-(3-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0412]

A.2-(3-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0413] A mixture of2-(3-methoxyphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl(0.030 mmol) (see Ex. 55, Part C), Toluene-4-sulfonic acid2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030mmol) (see Ex. 3, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(3-methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, 2H, J=8.60 Hz), 7.71 (d, 2H,J=8.60 Hz), 7.42-7.40 (m, 1H), 7.36-7.35 (m, 1H), 7.18-7.10 (m, 4H),6.81 (d, 2H, J=8.60 Hz), 6.61-6.59 (m, 1H), 6.49-6.45 (m, 2H), 4.21 (t,2H, J=6.26 Hz), 3.74 (s, 3H), 3.25 (d, 1H, J=14.08 Hz), 3.13 (d, 1H,J=14.08 Hz), 3.07 (t, 2H, J=6.26 Hz) 2.43 (s, 3H), 1.43 (s, 3H); HRMS(ES⁺) m/z exact mass calcd for C₃₃H₃₂NO₆S 570.1950, found 570.1950

Example 582-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

[0414]

A. 2-(Benzo[1,3]dioxol-5-yloxy)propionic acid ethyl ester

[0415] 5-Hydroxybenzo[1,3]dioxole (0.30 mol), Cs₂CO₃ (197.0 g, 0.61mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined inanhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere ofnitrogen. After 16 h, the DMF was removed in vacuo. The residue wasdissolved in ethyl acetate (300 mL) and washed twice with water and oncewith brine, The organic layer was dried over Na₂SO₄ and concentrated invacuo to produce an oil.

B.2-(Benzo[1,3]dioxol-5-yloxy)-3-(4-benzyloxyphenyl)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester

[0416] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solution2-(benzo[1,3]dioxol-5-yloxy)-propionic acid ethyl ester (24.7 mmol) inanhydrous THF (30 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After 5 min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) wasadded in one portion. After stirring for 10 min, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with ether (100 mL) and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (600 g silica,25×200 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) toprovide an oil as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(benzo[1,3]dioxol-5-yloxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

[0417]3-(4-Benzyloxyphenyl)-2-(benzo[1,3]dioxol-5-yloxy)-3-hydroxy-2-methylpropionicacid ethyl ester (13.4 mmol) in anhydrous CH₂Cl₂ (100 mL) and pyridine(134 mmol) was cooled to 0° C. and treated with trifluoroaceticanhydride (26.9 mmol). The mixture was stirred for 2 h and graduallywarmed to ambient temperature. An aqueous solution of 1N HCl (150 mL)was added and the mixture was stirred vigorously. The solution waspartitioned and the organic layer was washed twice with water and brine,dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester as an oil.

C. 2-(Benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester

[0418]3(4-Benzyloxyphenyl)-2-(benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionicacid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid: A mixture of2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-(benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (t, 1H, J=1.71 Hz), 7.91-7.89 (m,1H), 7.65-7.59 (m, 3H), 7.48 (t, 1H, J=7.57 Hz), 7.43-7.39 (m, 2H),7.35-7.31 (m, 1H), 7.13 (d, 2H, J=8.79 Hz), 6.79 (d, 2H, J=8.30 Hz),6.60 (d, I1H, J=8.30 Hz), 6.41 (d, 1H, J=2.44 Hz), 6.32 (dd, 1H, J=8.30Hz, J=2.44 Hz), 5.87 (d, 2H, J=0.98 Hz), 4.19 (t, 2H, J=6.35 Hz), 3.15(d, 1H, J=14.17 Hz), 304-2.99 (m, 3H), 2.38 (s, 3H), 1.30 (s, 3H); HRMS(ES⁺) m/z exact mass calcd for C₃₅H₃₂NO₇ 578.2179, found 578.2190.

Example 592-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

[0419]

A.2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

[0420] A mixture of2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (see Ex. 58, Part C), toluene-4-sulfonic acid2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (seeEx. 1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL)was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-(benzo[1,3]dioxol-5-yloxy)-3-}4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, 2H, J=8.79 Hz), 7.63 (d, 2H,J=8.31 Hz), 7.59 (d, 2H, J=8.79 Hz), 7.43-7.33 (m, 3H), 7.14 (d, 2H,J=8.79 Hz), 6.80 (d, 2H, J=8.30 Hz), 6.61 (d, 1H, J=8.79 Hz), 6.41 (d,1H, J=2.44 Hz), 6.32 (dd, 1H, J=8.30 Hz, J=2.44 Hz), 5.88 (s, 2H), 4.20(t, 2H, J=6.25 Hz), 3.05 (d, 1H, J=14.08 Hz), 3.04-2.99 (m, 3H), 2.37(s, 3H), 1.36 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₃₅H₃₂NO₇578.2179, found 578.2209

Example 602-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0421]

A.2-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

[0422] A mixture of2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acidethyl ester (0.030 mmol) (see Ex. 58, Part C), toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030mmol) (see Ex. 5, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-phenyl)-propionicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (t, 1H, J=1.71 Hz), 7.85-7.82 (m,1H), 7.67-7.63 (m, 1H), 7.42 (t, 1H, J=7.82 Hz), 7.38-7.37 (m, 1H),7.28-7.26 (m, 1H), 7.13 (d, 2H, J=8.79 Hz), 7.06 (dd, 1H, J=4.88 Hz,J=3.42 Hz), 6.79 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.30 Hz), 6.40 (d,1H, J=2.44 Hz), 6.32 (dd, 1H, J=8.30 Hz, J=2.44 Hz), 5.87 (d, 2H, J=0.98Hz), 4.19 (t, 2H, J=6.11 Hz), 3.15 (d, 1H, J=14.17 Hz), 3.04-3.01 (m,3H), 2.39 (s, 3H), 1.30 (s, 3H);HRMS (ES⁺) m/z exact mass calcd forC₃₃H₃₀NO₇S 584.1743, found 584.1744.

Example 612-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

[0423]

A. 2-Phenoxyhexanoic acid ethyl ester

[0424] Phenol (28.5 g, 0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromohexanoate (0.30 mol) were combined in anhydrous DMF (1000 mL) andstirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMFwas removed in vacuo. The residue was dissolved in ethyl acetate (300mL) and washed twice with water and once with brine. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to produce an oil.

B. 2-(4-Benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoicacid ethyl ester

[0425] A solution of LDA (16.5 mL, 24.7 mmol, 1.5M in cyclohexane) wascooled to −78° C. in a dry ice/acetone bath and then added to a solutionof 2-phenoxyhexanoic acid ethyl ester (24.7 mmol) in anhydrous THF (30mL) also cooled to −78° C. under an atmosphere of nitrogen. After 5 min,4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added in one portion.After stirring for 10 min, the reaction mixture was quenched withsaturated solution of aqueous NH₄Cl (10 mL) and the mixture allowed towarm to ambient temperature. The biphasic mixture was diluted with ether(100 mL) and partitioned, and the organic layer was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified byflash column chromatography (600 g silica, 25×200 mL fractions, gradientelution 0-20% ethyl acetate in hexanes) to provide an oil as a mixtureof inseparable diastereomers of2-[(4-benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-hexanoic acid ethylester which was used without further characterization or purification.

[0426] 2-[(4-Benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-hexanoic acidethyl ester (13.4 mmol) in anhydrous CH₂Cl₂ (100 mL) and pyridine (134mmol) was cooled to 0° C. and treated with trifluoroacetic anhydride(26.9 mmol). The mixture was stirred for 2 h and gradually warmed toambient temperature. An aqueous solution of 1N HCl (150 mL) was addedand the mixture was stirred vigorously. The solution was partitioned andthe organic layer was washed twice with water and brine, dried overNa₂SO₄, and concentrated in vacuo to produce2-(4-benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoic acidethyl ester as an oil.

C. 2-(4-Hydroxybenzyl)-2-phenoxyhexanoic acid ethyl ester

[0427]2-(4-Benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoic acidethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) andtreated with 5% palladium on carbon (300 mg), and stirred under anatmosphere of hydrogen for 20 h. The suspension was filtered throughcelite and concentrated in vacuo to an oil.

D.2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

[0428] A mixture of 2-(4-hydroxybenzyl)-2-phenoxyhexanoic acid ethylester (0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-biphenylyl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.1, Part I) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, 2H, J=8.60 Hz), 7.65-7.61 (m,4H), 7.46 (t, 2H, J=7.62 Hz), 7.38-7.26 (m, 3H), 7.07-6.96 (m, 5H), 6.76(d, 2H, J=8.60 Hz), 4.18 (t, 2H, J=6.65 Hz), 3.29 (s, 2H), 2.97 (t, 2H,J=6.65 Hz), 2.38 (s, 3H), 2.08-1.98 (m, 2H), 1.42-1.18 (m, 4H), 0.79 (t,3H, J=7.04 Hz); MS (ES⁺) calcd for C₃₇H₃₈NO₅: Found m/e 576.3 (M+1,100%).

Example 622-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

[0429]

A.2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

[0430] A mixture of 2-(4-hydroxybenzyl)-2-phenoxyhexanoic acid ethylester (0.030 mmol) (see Ex 61, Part C), toluene-4-sulfonic acid2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex.2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) washeated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) andadditional ethanol (1 mL) was added to the reaction mixture and it washeated at reflux for an additional 2 h. The reaction was cooled and thesolvent removed in vacuo. The residue was acidified with aqueous 1 N HCl(5 mL), extracted with water and CH₂Cl₂ and the organic layer dried bypassing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (t, 1H, J=1.56 Hz), 7.86 (d, 1H,J=7.82 Hz), 7.58-7.54 (m, 3H), 7.42-7.35 (m, 3H), 7.30-7.18 (m, 3H),6.97 (t, 1H, J=7.23 Hz), 6.93-6.87 (m, 4H), 6.68 (d, 2H, J=8.60 Hz),4.11 (t, 2H, J=6.65 Hz), 3.21 (s, 2H), 2.89 (t, 2H, J=6.65 Hz), 2.29 (s,3H), 2.02-1.89 (m, 2H), 1.33-1.09 (m, 4H), 0.71 (t, 3H, J=7.04 Hz); MS(ES⁺) calcd for C₃₇H₃₈NO₅: Found m/e 576.3 (M+1, 100%).

Example 632-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid

[0431]

A.2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid

[0432] A mixture of 2-(4-hydroxybenzyl)-2-phenoxyhexanoic acid ethylester (0.030 mmol) (see Ex 61, Part C), toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030mmol) (see Ex. 5, Part B) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) inethanol (2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH(0.5 mL) and additional ethanol (1 mL) was added to the reaction mixtureand it was heated at reflux for an additional 2 h. The reaction wascooled and the solvent removed in vacuo. The residue was acidified withaqueous 1 N HCl (5 mL), extracted with water and CH₂Cl₂ and the organiclayer dried by passing it through a Varian Chem Elut 1003 cartridge. Thesolvent was removed in vacuo to give2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.15-8.12 (m, 1H), 7.79 (d, 1H, J=7.43Hz), 7.57 (d, 1H, J=7.82 Hz), 7.37-7.32 (m, 2H), 7.24-7.18 (m, 3H), 7.01(dd, 1H, J=5.08 Hz, J=3.52 Hz), 6.99-6.87 (m, 5H), 6.68 (d, 2H, J=8.99Hz), 4.10 (t, 2H, J=6.65 Hz), 3.21 (s, 2H), 2.91 (t, 2H, J=6.65 Hz),2.31 (s, 3H), 2.02-1.88 (m, 2H), 1.34-1.08 (m, 4H), 0.71 (t, 3H, J=7.04Hz); MS (ES⁺) calcd for C₃₅H₃6ON₅S: Found m/e 582.2 (M+1, 100%).

Example 643-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid

[0433]

A.3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid

[0434] A mixture 2-(p-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionicacid ethyl ester (0.030 mmol) (see Ex 35, Part D), toluene-4-sulfonicacid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol)(see Ex. 2, Part F) and 325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol(2 mL) was heated to reflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL)and additional ethanol (1 mL) was added to the reaction mixture and itwas heated at reflux for an additional 2 h. The reaction was cooled andthe solvent removed in vacuo. The residue was acidified with aqueous 1 NHCl (5 mL), extracted with water and CH₂Cl₂ and the organic layer driedby passing it through a Varian Chem Elut 1003 cartridge. The solvent wasremoved in vacuo to give3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid.

[0435] The compound in Table 1 were made by the methods discribed above:EXAMPLE STRUCTURAL FORMULA 65

66

67

68

Example 713-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4yl)-ethoxy]-phenyl}-2-(2-methoxy-phenoxy)-2-methyl-propionicacid

[0436]

[0437] 2-(2-Methoxy-phenoxy)-propionic acid ethyl ester: Cesiumcarbonate (53.86 g, 165.3 mmol) was added to a solution of2-methoxyphenol (10.26 g, 82.6 mmol) in anhydrous DMF (500 mL) at roomtemperature under an atmosphere of nitrogen. After five minutes, ethyl2-bromopropionate (10.7 mL, 82.6 mmol, d=1.394) was added rapidlydropwise and the resultant mixture was allowed to stir at 90° C. for 18h. The reaction mixture was diluted with diethyl ether, then extractedtwice with 1N HCl and twice with water. The organic layer was dried overMgSO₄ and concentrated in vacuo. The residue was purified by flashchromatography (25% ether in hexanes) to provide the titled compound(16.97 g, 92%) as a light yellow oil.¹H NMR (400 MHz, CDCl₃): δ6.96-6.80 (m, 4H), 4.73 (q, 1H, J=7.04 Hz), 4.23-4.12 (m, 2H), 3.82 (s,3H), 1.62 (d, 3H, J=6.65 Hz), 1.21(t, 3H, J=7.04 Hz). MS [ES+] m/z exactmass calcd for C₁₂H₁₇O₄ 225.1127, found 225.1110. R_(f)=0.19 in 25%ether in hexanes.

[0438]3-(4-Benzyloxy-phenyl)-3hydroxy-2-(2-methoxy-phenoxy)-2-methyl-propionicacid ethyl ester: A solution of LDA (32.1 mL, 107.1 mmol, 1.5M incyclohexane) in anhydrous THF (60 mL) was cooled to −78° C. in a dryice/acetone bath and added to a solution of2-(2-Methoxy-phenoxy)-propionic acid ethyl ester in anhydrous THF (60mL) also cooled to −78° C. under an atmosphere of nitrogen. After fiveminutes, 4-benzyloxybenzaldehyde (5.11 g, 24.1 mmol) was added in oneportion. After stirring for one minute, the reaction mixture wasquenched with acetic acid (4.6 mL, 80.3 mmol, d=1.049) and a saturatedsolution of aqueous NH₄Cl (50 mL). The biphasic mixture was allowed towarm to room temperature and diluted with diethyl ether (1L). Theorganic layer was washed with water, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash column chromatography (20%ethyl acetate in hexanes) to provide a mixture of diastereomers of3-(4-Benzyloxy-phenyl)-3-hydroxy-2-(2-methoxy-phenoxy)-2-methyl-propionicacid ethyl ester (7.62 g, 65%).¹H NMR (400 MHz, CDCl₃): δ 7.53-7.34 (m,5H), 7.09-7.00 (m, 2H), 6.91-6.86(m, 2H), 6.78(td, 1H, J=8.0 Hz, 1.6Hz), 6.65(dd, 1H, J=8.0 Hz, 1.6 Hz), 6.44-6.43 (m, 3H), 5.12-5.08 (m,2H), 4.39-4.18 (m, 2H), 3.72-3.67 (m, 3H), 1.41 (s, 1H), 1.34-1.26 (m,6H). R_(f)=0.42 in 25% ethyl acetate in hexanes.

[0439]3-(4-Benzyloxy-phenyl)-2-(2methoxy-phenoxy)-2-methyl-3-(2,2,2-trifluoro-acetoxy)-propionicacid ethyl ester:3-(4-Benzyloxy-phenyl)-3-hydroxy-2-(2-methoxy-phenoxy)-2-methyl-propionicacid ethyl ester (7.62 g, 17.5 mmol) in anhydrous CH₂Cl₂ (150 mL) wascooled to 0° C. and treated with pyridine (14 mL, 174.6 mmol, d=0.987).Trifluoroacetic anhydride (7.4 mL, 52.4 mmol, d=1.487) was addeddropwise and the mixture was stirred for 2 h, gradually warming toambient temperature, The reaction mixture was diluted with diethyl etherand washed with 1N HCl, then water. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to provide the titled compound (8.77 g,100%) which was used without purification.

[0440] 3-(4-Hydroxy-phenyl)-2-(2methoxy-phenoxy)-2-methyl-propionic acidethyl ester:3-(4-Benzyloxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-3-(2,2,2-trifluoro-acetoxy)-propionicacid ethyl ester was dissolved in ethyl acetate (350 mL), treated with5% palladium on carbon (8.77 g), and stirred under an atmosphere ofhydrogen for 48 h. The suspension was filtered through celite andconcentrated in vacuo. The residue was purified by flash columnchromatography (25% ethyl acetate in hexanes) to provide the titlecompound as a light yellow oil (1.73 g, 25%). ¹H NMR (400 MHz, CDCl₃): δ7.12 (d, 2H, J=6.65 Hz), 6.98-6.93 (m, 5H), 4.24-4.15 (m, 2H), 3.75 (s,3H), 3.23 (d; 1H, J=13.69 Hz), 3.13 (d, 1H, J=13.69 Hz), 1.30 (s, 3H),1.22 (t, 3H, J=7.43 Hz). MS [EI+] 331 (M+H)⁺, [EI−] 329 (M−H)⁺.R_(f)=0.14 in 25% ethyl acetate in hexanes.

[0441]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2-methoxy-phenoxy)-2-methyl-propionicacid; Potassium carbonate (0.048 g, 0.35 mmol) was added to a solutionof 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acidethyl ester and toluene-4-sulfonic acid2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester in 4A sieve-driedethanol (2 mL). The resultant mixture was stirred at 80° C. under anatmosphere of nitrogen for 18 h, then diluted with ethanol (2 mL). 5NNaOH (0.5 mL) was added, then the reaction mixture was refluxed for 2 h.The reaction mixture was concentrated in vacuo, diluted with 1N HCl, andextracted with CH₂Cl₂. The organic layer was dried through a VarianChemElut cartridge, concentrated in vacuo, and purified by LCMS. ¹H NMR(400 MHz, CDCl₃): δ 8.05 (d, 2H, J=7.82 Hz), 7.70 (d, 2H, J=8.21 Hz),7.62 (d, 2H, J=7.82 Hz), 7.45 (t, 2H, J=7.82 Hz), 7.39-7.36 (m, 1H),7.19 (d, 2H, J=8.21), 6.88 (d, 1H, J=8.21 Hz), 6.84-6.80 (m, 3H), 6.63(d, 1H, J=7.82 Hz), 4.22 (t, 2H, J=5.87 Hz), 3.82 (s, 3H), 3.30 (d, 1H,J=14.08 Hz), 3.08 (dd, 3H, J=9.78 Hz, 3.52 Hz), 2.43 (s, 3H), 1.30(s,2H), 1.23 (s, 1H). MS [ES+] m/z exact mass calcd for C35H34NO6 564.2386,found 564.2407.

Example 72

[0442]

[0443]2-(2-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-phenyl)-propionicacid;: The title compound was prepared using the representative StandardProcedure (E) from3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethyl ester. ¹H NMR(400 MHz, CDCl₃): δ 8.05 (d, 2H, J=7.82 Hz), 7.86 (d, 2H, J=8.21 Hz),7.68 (d, 2H, J=7.82 Hz), 7.45 (t, 1H, J=7.65 Hz), 7.41-7.40 (m, 1H),7.31-7.30 (m, 1H), 7.19(d, 1H, J=8.40 Hz), 7.10-7.04 (m, 2H), 6.88-6.79(m, 2H), 6.61 (dd, 1H, J=8.40 Hz, 1.65 Hz), 4.22 (t, 2H, J=5.87 Hz),3.82 (s, 3H), 3.30 (d, 1H, J=14.08 Hz), 3.10-3.03 (m, 3H), 2.43 (s, 3H),1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C₃₃H₃₂NO₆S 570.1950,found 570.1958.

Example 72

[0444]

[0445]3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-o-tolyloxy-propionicacid: The title compound was prepared using the representative StandardProcedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃): δ 8.02 (d, 2H, J=8.21 Hz), 7.65 (d, 2H, J=8.60 Hz), 7.61 (d, 2H,J=7.04 Hz), 7.44 (t, 2H, J=7.43 Hz), 7.38-7.34 (m, 1H), 7.13 (d, 3H,J=8.60 Hz), 7.09-7.05 (d, 3H), 7.09-7.05 (m, 1H), 6.91(t, 1H, J=7.04Hz), 6.82-6.79 (m, 3H), 4.19 (t, 2H, J=6.65 Hz), 3.27 (d, 1H, J=14.08Hz), 3.19 (d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.26 Hz), 2.39* (s, 3H),2.17 (s, 3H), 1.49 (s, 3H). MS [EI+] 548 (M+H)⁺, [EI−] 546 (M−H)⁺.

Example 74 Binding and Cotransfection Studies

[0446] DNA-dependent binding (ABCD binding) was carried out using SPAtechnology with PPAR receptors. Tritium-labeled PPARα and PPARγ agonistswere used as radioligands for generating displacement curves and IC₅₀values with compounds of the invention. Cotransfection assays werecarried out in CV-1 cells. The reporter plasmid contained an acylCoAoxidase (AOX) PPRE and TK promoter upstream of the luciferase reportercDNA. Appropriate PPARs and RXRα were constitutively expressed usingplasmids containing the CMV promoter. For PPARα and PPARγ, interferenceby endogenous PPARγ in CV-1 cells was an issue. In order to eliminatesuch interference, a GAL4 chimeric system was used in which the DNAbinding domain of the transfected PPAR was replaced by that of GAL4, andthe GAL4 response element was utilized in place of the AOX PPRE.Cotransfection efficacy was determined relative to PPARα agonist andPPARβ agonist reference molecules. Efficacies were determined bycomputer fit to a concentration-response curve, or in some cases at asingle high concentration of agonist (10 μM). For binding orcotransfection studies with receptors other than PPARs, similar assayswere carried out using appropriate ligands, receptors, reporterconstructs, etc., for that particular receptor.

[0447] These studies were carried out to evaluate the ability ofcompounds of the invention to bind to and/or activate various nucleartranscription factors, particularly huPPARα: (“hu” indicates “human”)and huPPARγ. These studies provide in vitro data concerning efficacy andselectivity of compounds of the invention. Furthermore, binding andcotransfection data for compounds of the invention were compared withcorresponding data for marketed compounds that act on either huPPARα orhuPPARγ.

[0448] Binding and cotransfection data for representative compounds ofthe invention are compared with corresponding data for referencecompounds in Table 2. TABLE 2 Comparison of binding IC₅₀ values andcotransfection efficacy data of compounds of the invention to referencecompounds. huPPARα huPPARγ CTF Efficacy CTF Efficacy Example IC₅₀(nM)(%) IC₅₀(nM) (%)  4 147 38 41 93  7 4124 60 174 93  8 605 45 41 91 15196 96 107 90 17 186 116 119 80 22 260 63 78 100 26 159 54 55 100 34 16561 40 95 41 402 44 45 108 42 310 49 56 105 48 182 45 54 145 51 203 43 56160 56 613 70 99 88 58 145 48 37 101 Troglita- 94,500 0 1180 80 zoneFenofibric 68,000 16 125,000 0 acid

Example 75 Evaluation of Triglyceride and Cholesterol Levels in Hu apoAITransgenic Mice

[0449] Five to six week old male mice, transgenic for human apoAI[C57B1/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.] werehoused five per cage (10″×20″8″ with aspen chip bedding) with food(Purina 5001) and water available at all times. After an acclimationperiod of 2 weeks, animals were individually identified by ear notches,weighed, and assigned to groups based on body weight. Beginning thefollowing morning, mice were dosed daily by oral gavage for 7 days usinga 20 gauge, 1½″ curved disposable feeding needle (Popper & Sons).Treatments were test compounds (30 mg/kg), a positive control(fenofibrate, 100 mg/kg) or vehicle [1% carboxymethylcellulose(w/v)/0.25% Tween80 (w/v); 0.2 ml/mouse]. Prior to termination on day 7,mice were weighed and dosed. Three hours after dosing, animals wereanesthetized by inhalation of isoflurane (2-4%; Abbott Laboratories,Chicago, Ill.) and blood obtained via cardiac puncture (0.7-1.0 ml).Whole blood was transferred to serum separator tubes (Vacutainer SST),chilled on ice, and permitted to clot. Serum was obtained aftercentrifugation at 4° C. and frozen until analysis for triglycerides,total cholesterol, compound levels, and serum lipoprotein profile byfast protein liquid chromatography (FPLC) coupled to an inline detectionsystem. After sacrifice by cervical dislocation, the liver, heart andepididymal fat pads were excised and weighed.

[0450] The animals dosed with vehicle had average triglycerides valuesof 60-80 mg/dl, which were reduced by the positive control fenofibrate(33-58 mg/dl with a mean reduction of 37%). The animals dosed withvehicle had average total serum cholesterol values of 140-180 mg/dl,which were increased by fenofibrate (190-280 mg/dl, with a meanelevation of 41%). When subject to EPLC analysis, pooled sera fromvehicle-treated hu apoAl transgenic mice had a high density lipoproteincholesterol (HDLc) peak area which ranged from 47 v-sec to 62 v-sec.Penofibrate increased the amount of HDLc (68-96 v-sec with a meanpercent increase of 48%). Test compounds are reported in terms ofpercent increase in the area under the curve as indicated in Table 3.TABLE 3 Percent increase of HDLc serum levels in mice receiving acompound of the invention over mice receiving vehicle. Example % HDLcIncrease 4 40.4 5 94.5 19 85.3

Example 76 Evaluation of Glucose Levels in db/db Mice

[0451] Five week old male diabetic (db/db) mice [C57BlKs/j-m +/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or lean littermates(DB/?) were housed 6 per cage (10″20″8″ with aspen chip bedding) withfood (Purina 5015) and water available at all times. After anacclimation period of 2 weeks, animals were individually identified byear notches, weighed, and bled via the tail vein for determination ofinitial glucose levels. Blood was collected (100 μl) from unfastedanimals by wrapping each mouse in a towel, cutting the tip of the tailwith a scalpel, and milking blood from the tail into a heparinizedcapillary tube (Fisher) balanced on the edge of the bench. Sample wasdischarged into a heparinized microtainer with gel separator (VWR) andretained on ice. Plasma was obtained after centrifugation at 4° C. andglucose measured immediately. Remaining plasma was frozen until thecompletion of the experiment, when glucose and triglycerides wereassayed in all samples. Animals were grouped based on initial glucoselevels and body weights. Beginning the following morning, mice weredosed daily by oral gavage for 7 days using a 20 gauge, 1½″ curveddisposable feeding needle. Treatments were test compounds (30 mg/kg), apositive control agent (30 mg/kg) or vehicle [1% carboxymethylcellulose(w/v)/0.25% Tween80 (w/v); 0.3 ml/mouse]. On day 7, mice were weighedand bled (tail vein) 3 hours after dosing. Twenty-four hours after the7^(th) dose (i.e., day 8), animals were bled again (tail vein). Samplesobtained from conscious animals on days 0, 7 and 8 were assayed forglucose. After the 24 hour bleed, animals were weighed and dosed for thefinal time. Three hours after dosing on day 8, animals were anesthetizedby inhalation of isoflurane and blood obtained via cardiac puncture(0.5-0.7 ml). Whole blood was transferred to serum separator tubes,chilled on ice and permitted to clot. Serum was obtained aftercentrifugation at 4° C. and frozen until analysis for compound levels.After sacrifice by cervical dislocation, the liver, heart and epididymalfat pads were excised and weighed.

[0452] The animals dosed with vehicle had average triglycerides valuesof 170-230 mg/dl, which were reduced by the positive PPARα (70-120 mg/dlwith a mean reduction of 50%). Male db/db mice were hyperglycemic(average glucose of 680-730 mg/dl on the 7^(th) day of treatment), whilelean animals had average glucose levels between 190-230 mg/dl. Treatmentwith the positive control agent reduced glucose significantly (350-550mg/dl with a mean decrease towards normalization of 56%). Test compoundsare reported in Table 4 in terms of glucose normalization (i.e., 100%normalization would be glucose levels in treated db/db mice which didnot differ from lean values.

[0453] Glucose was measured colorimetrically using commerciallypurchased reagents (Sigma #315-500). According to the manufacturers, theprocedures were modified from published work (McGowan, M. W., Artiss, J.D., Strandbergh, D. R. & Zak, B. Clin Chem, 20:470-5 (1974) and Keston,A. Specific colorimetric enzymatic analytical reagents for glucose.Abstract of papers 129th Meeting ACS, 31C (1956).); and depend on therelease of a mole of hydrogen peroxide for each mole of analyte, coupledwith a color reaction first described by Trinder (Trinder, P.Determination of glucose in blood using glucose oxidase with analternative oxygen acceptor. Ann Clin Biochem, 6:24 (1969)). Theabsorbance of the dye produced is linearly related to the analyte in thesample. The assays were further modified in our laboratory for use in a96 well format. Standards (Sigma #339-11, Sigma #16-11, and Sigma#CC0534 for glucose, triglycerides and total cholesterol, respectively),quality control plasma (Sigma # A2034), and samples (2 or 5 μl/well)were measured in duplicate using 200 μl of reagent. An additionalaliquot of sample, pipetted to a third well and diluted in 200 μl water,provided a blank for each specimen. Plates were incubated at roomtemperature (18, 15, and 10 minutes for glucose, triglycerides and totalcholesterol, respectively) on a plate shaker (DPC Micormix 5) andabsorbance read at 500 nm (glucose and total cholesterol) or 540 nm(triglycerides) on a plate reader (Wallac Victor 1420). Sampleabsorbances were compared to a standard curve (100-800, 10-500, and100-400 mg/dl for glucose, triglycerides and total cholesterol,respectively). Values for the quality control sample were always withinthe expected range and the coefficient of variation for samples wasbelow 10%. All samples from an experiment were assayed at the same timeto minimize inter-assay variability.

[0454] Serum lipoproteins were separated and cholesterol quantitatedwith an in-line detection system. Sample was applied to a Superose® 6 HR10/30 size exclusion column (Amersham Pharmacia Biotech) and eluted withphosphate buffered saline-EDTA at 0.5 ml/min. Cholesterol reagent (RocheDiagnostics Chol/HP 704036) at 0.16 ml/min mixed with the columneffluent through a T-connection and the mixture passed through a 15m×0.5 mm id knitted tubing reactor immersed in a 37 C. water bath. Thecolored product produced in the presence of cholesterol was monitored inthe flow stream at 505 nm and the analog voltage from the monitor wasconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration was plottedvs time and the area under the curve corresponding to the elution ofVLDL, LDL and HDL was calculated using Perkin Elmer Turbochromesoftware. TABLE 4 Percent glucose normalisation values in db/db mice.Example Glucose Normalisation 4 91 5 71

[0455] Equivalents

[0456] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound represented by the followingstructural formula:

and pharmaceutically acceptable salts thereof, wherein: n is2, 3,or 4;R₁ is H, a C1-C4 alkyl, phenyl or C1-C4 haloalkyl; R₂ are each,independently, H, a C₁-C6 alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, acycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with thephenyl to which they are bound form naphthyl or1,2,3,4tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6 alkyl,a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl,or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently, H, asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 2. The compound of claim 1, wherein n is
 2. 3.The compound of claim 2, wherein the compound is represented by thefollowing structural formula:

wherein R₁₁ are each, independently, H, a halo, a C1-C4 alkyl, or aC1-C4 alkoxy.
 4. The compound of claim 3, wherein R₁ is methyl.
 5. Thecompound of claim 4, wherein R₇ and R₈ are each H.
 6. The compound ofclaim 2, wherein the compound is represented by the following structuralformula:

wherein, R₁₂ are each, independently, H, a halo, a C1-C4 alkyl, or aC1-C4 alkoxy.
 7. The compound of claim 6, wherein R₁ is methyl.
 8. Thecompound of claim 7, wherein R₇ and R₈ are each H.
 9. The compound ofclaim 2, wherein the compound is represented by the following structuralformula:


10. A compound selected from the group consisting of:3-{4-[2-(2-Biphenyl4-yl-5-methyl-oxazol-4yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxyl-phenyl}-2-methyl-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-phenyl)-2-phenoxypropionicacid;3-(4-{(2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxylphenyl)-2-methyl-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxylphenyl)-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxyl-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyloxazol-4-yl)ethoxyl-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid;3-(3-Methoxy-4-{2-[5-methyl-2-(4-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-3-propyl-phenyl)-2-phenoxy-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol4-yl)-ethoxy]-naphthalen-1-yl)-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methyl-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid;2-(3-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxyl-phenyl}-2-(3-tert-butyl-phenoxy)-2-methyl-propionicacid;2-(3-tert-Butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol4-yl]-ethoxy}-phenyl)-propionicacid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-(4-Chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid;2-(4-Cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid; 3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionic acid;2-(3,4-Dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid;(R)-2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy-propionicacid;(R)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid;2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid;2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid;2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid;2-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxyl-phenyl}-2-methyl-2-m-tolyloxy-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-m-tolyloxy-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;2-(4-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid;2-(3-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid;2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid;2-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid;2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid;2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid; and(R)-3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid.
 11. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and at least one compound represented by thefollowing structural formula:

and pharmaceutically acceptable salts thereof, wherein: n is 2, 3, or4;R₁ is H, a C1-C4 alkyl, phenyl or C1-C4 haloalkyl; R₂ are each,independently, H, a C1-C6 alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, acycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with thephenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 12. The pharmaceutical composition of claim 11,wherein n is
 2. 13. The pharmaceutical composition of claim 12, whereinthe compound is represented by the following structural formula:

wherein R₁₁ are each, independently, H, a halo, a C1-C4 alkyl, or aC1-C4 alkoxy.
 14. The pharmaceutical composition of claim 13, wherein R₁is methyl.
 15. The pharmaceutical composition of claim 14, wherein R₇and R₈ are each H.
 16. The pharmaceutical composition of claim 12,wherein the compound is represented by the following structural formula:

wherein, R₁₂ are each, independently, H, a halo, a C1-C4 alkyl, or aC1-C4 alkoxy.
 17. The pharmaceutical composition of claim 16, wherein R₁is methyl.
 18. The pharmaceutical composition of claim 17, wherein R₇and R₈ are each H.
 19. The pharmaceutical composition of claim 12,wherein the compound is represented by the following structural formula:


20. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and at least one compound selected from the groupconsisting of:3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid;3-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl4-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid;3-(3-Methoxy-4-{2-[5-methyl-2-(4-thiophen-2-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-3-propyl-phenyl)-2-phenoxy-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl)-2-methyl-2-phenoxypropionic acid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl)-2-methyl-2-phenoxypropionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-phenoxypropionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionicacid;2-(3-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-tert-butyl-phenoxy)-2-methyl-propionicacid;2-(3-tert-Butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-(4-Chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4chloro-phenoxy)-2-methyl-propionicacid;2-(4-Cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid;2-(3,4-Dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid;(R)-2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy-propionicacid;(R)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid;2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid;2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid;2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid; 3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(b3,4-difluoro-phenoxy)-2-methyl-propionic acid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid;2-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-2-m-tolyloxy-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;2-(4-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-Methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid;3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid;3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid;2-(3-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid;2-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-methyl-propionicacid;2-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid;2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid;2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid;2-(4-{2-[5-Methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid; and(R)-3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid.
 21. A method of modulating a peroxisome proliferator activatedreceptor, comprising the step of contacting the receptor with at leastone compound represented by the following structural formula:

and pharmaceutically acceptable slats, solvates and hydrates thereof,wherein; n is 2, 3 or 4; R₁ is H, a C1-C4 alkyl, phenyl or C1-C4haloalkyl; R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 22. The method of claim 21, wherein theperoxisome proliferator activated receptor is an α receptor.
 23. Themethod of claim 21, wherein the peroxisome proliferator activatedreceptor is an γ receptor.
 24. A method of treating or preventingdiabetes mellitus in a mammal, comprising the step of administering tothe mammal a therapeutically effective amount of at least one compoundrepresented by the following structural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: n is 2, 3, or 4; R₁ is H, a C1-C4 alkyl, phenyl or C1-C4haloalkyl; R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 25. The method of claim 24, wherein the mammalis a human.
 26. The method of claim 24, wherein the compound potentiatesa peroxisome proliferator activated receptor.
 27. The method of claim26, wherein the peroxisome proliferator activated receptor is a γreceptor.
 28. The method of claim 26, wherein the compound lowers bloodglucose levels.
 29. A method of treating or preventing cardiovasculardisease in a mammal, comprising the step of administering to the mammala therapeutically effective amount of at least one compound representedby the following structural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: n is 2, 3, or 4; R₁ is H, a C1-C4 alkyl, phenyl or C1-C4haloalkyl; R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 30. The method of claim 29, wherein the mammalis a human.
 31. The method of claim 29, wherein the compound potentiatesa peroxisome proliferator activated receptor.
 32. The method of claim31, wherein the peroxisome proliferator activated receptor is an αreceptor.
 33. The method of claim 31, wherein the compound lowerstriglycerides in the mammal.
 34. The method of claim 31, wherein thecompound lowers low density lipoproteins in the mammal.
 35. The methodof claim 31, wherein the compound increases high density lipoproteins ina mammal.
 36. A method of treating or preventing Syndrome X in a mammal,comprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound represented by the followingstructural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: n is 2, 3, or 4; R₁ is H, a C1-C4 alkyl, phenyl or C1-C4haloalkyl; R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 37. The method of claim 36, wherein thecompound potentiates a peroxisome proliferator activated receptor. 38.The method of claim 37, wherein the compound lowers blood glucoselevels,
 39. The method of claim 37, wherein the compound lowers serumconcentration of triglycerides in the mammal.
 40. The method of claim37, wherein the compound lowers serum concentration of low densitylipoproteins in the mammal.
 41. The method of claim 37, wherein thecompound increases serum concentration of high density lipoproteins in amammal.
 42. A compound for use in therapy for a disorder modulated by aperoxisome proliferator activated receptor, wherein the compound isrepresented by the following structural formula:

and pharmaceutically acceptable salts thereof, wherein: n is 2, 3, or 4;R₁ is H, a C1-C4 alkyl, phenyl or C1-C4 haloalkyl; R₂ are each,independently, H, a C1-C6 alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, acycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with thephenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 43. Use of a compound for the manufacture of amedicament for the treatment of a condition modulated by a peroxisomeproliferator activated receptor, wherein the compound is represented bythe following structural formula:

and pharmaceutically acceptable salts thereof, wherein: n is 2, 3, or 4;R₁ is H, a C1-C4 alkyl, phenyl or C1-C4 haloalkyl; R₂ are each,independently, H, a C1-C6 alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, acycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with thephenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R₇ are each, independently, H, aC1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4haloalkoxy, or a cycloalkyl; and R₈ are each, independently, H, a C1-C4alkyl, a C1-C4 alkoxy, a halo, a C1-C4 haloalkyl, a C1-C4 haloalkoxy, acycloalkyl, or each R₈ taken together with the phenyl to which they areattach is benzodioxolyl.
 44. A method of preparing a2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole represented bythe following structural formula:

wherein: R₁ is H, a C1-C4 alkyl, phenyl or C1-C4 haloalkyl; R₅ are each,independently, H, a substituted or unsubstituted aryl or a substitutedor unsubstituted heteroaryl, comprising the steps of: a) condensing adionemonooxime represented by the following structural formula:

 with a bromobenzaldehyde represented by the following formula:

 in the presence of an acid to form an oxazole N-oxide represented bythe following structural formula:

b) treating the oxazole N-oxide with phosphorous oxychloride to form a2-(bromophenyl)-4-chloromethyl-5-substituted-oxazole represented by thefollowing structural formula:

c) treating the 2-(bromophenyl)-4-chloromethyl-5-substituted-oxazolewith a cyanide salt and an iodide salt to form2-(bromophenyl)-4cyanomethyl-5-substituted-oxazole represented by thefollowing structural formula:

d) treating the 2-(bromophenyl)-4-cyanomethyl-5-substituted-oxazole withan alkali metal hydroxide to form2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazole represented by thefollowing structural formula:

e) treating the 2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazolewith boron trifluoride to form a2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole represented bythe following structural formula:


45. The method of claim 44, further comprising the steps of a) treatingthe a 2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole with asulfonyl halide or a sulfonyl anhydride in the presence of a base toform a 2-(bromophenyl-5-substituted-oxazol-4-yl)ethyl sulfonyl esterrepresented by the following structural formula:

wherein R₉ is methyl or tolyl; b) reacting the2-(bromophenyl-5-substituted-oxazol-4-yl)ethyl sulfonyl ester with acompound represented by the following structural formula:  in thepresence of an alkali metal carbonate to form a3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by the following structural formula:

 wherein: R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₇ areeach, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4haloalkyl, a C1-C4 haloalkoxy, or a cycloalkyl; R₈ are each,independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4haloalkyl, a C1-C4 haloalkoxy, a cycloalkyl, or each R₈ taken togetherwith the phenyl to which they are attach is benzodioxolyl; and R₁₀ is aC1-C4 alkyl; and c) treating the3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester with an aryl boronic acid in the presence oftriphenylphosphine, palladium acetate and sodium carbonate to form a3-(4-{2-[2-(arylphenyl)-5-substituted-oxazol4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by the following structural formula:


46. The method of claim 45, further comprising the step of treating the3-(4-{2-[2-(arylphenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester with an alkali metal hydroxide to form a3-(4-{2-[2-(arylphenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid represented by the following structural formula:


47. The method of claim 44, further comprising the steps of: a) treatingthe 2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole with anaryl boronic acid in the presence of triphenylphosphine, palladiumacetate and sodium carbonate to form a2-(arylphenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole represented bythe following structural formula:

b) treating the a2-(arylphenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole with a sulfonylhalide or a sulfonyl anhydride in the presence of a base to form a2-(arylphenyl-5-substituted-oxazol-4-yl)ethyl sulfonyl ester representedby the following structural formula:

wherein R₉ is methyl or tolyl; c) reacting the2-(arylphenyl-5-substituted-oxazol4-yl)ethyl sulfonyl ester with acompound represented by the following structural formula:

 in the presence of cesium carbonate to form a3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester represented by the following structural formula:

wherein: R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one or R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₇ areeach, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4haloalkyl, a C1-C4 haloalkoxy, or a cycloalkyl; R₈ are each,independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, a C1-C4haloalkyl, a C1-C4 haloalkoxy, a cycloalkyl, or each R₈ taken togetherwith the phenyl to which they are attach is benzodioxolyl; and R₁₀ is aC1-C4 alkyl group.
 48. The method of claim 47, further comprising thestep of treating the3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid ester with an alkali metal hydroxide to form a3-(4-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoicacid represented by the following structural formula:


49. All methods disclosed herein of preparing the compounds representedby Structural Formula I.
 50. A compound as claimed by claim 1 selectedfrom the group consisting of:3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-o-tolyloxy-propionicacid,3-{4-[2-(2-Biphenyl4-yl-5-methyloxazol-4-yl)-ethoxy]-phenyl}-2-(2-methoxy-phenoxy)-2-methyl-propionicacid, and2-(2-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid.
 51. A compound of Formula Ia and pharmaceutically acceptablesalts, solvates and hydrates thereof:

Wherein: n is 1, 2, 3, or 4; R₁ is H, a C1-C4 alkyl, phenyl or C1-C4haloalkyl; R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R₆ isH, a C1-C4 alkyl, or an aminoalkyl; R14 is substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl; and R15 is substituted orunsubstituted (CH₂).
 52. A compound of claim 51 wherein R14 is

wherein R₇ are each, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, ahalo, C1-C4 haloalkyl, C1-C4 haloalkoxyl, heterocycle, or a cycloalkyl;and R₈ are each, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, ahalo, C1-C4 haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, Heterocyclic oreach R₈ taken together with the phenyl to which they are attached arebenzodioxolyl.
 53. A compound of claim 51 wherein R14 is:

wherein R₇ are each, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, ahalo, Cl-C4 haloalkyl, C1-C4 haloalkoxyl, heterocycle, or a cycloalkyl;and R₈ are each, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, ahalo, C1-C4 haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, Heterocyclic, oreach R₈ taken together with the phenyl to which they are attached arebenzodioxolyl.
 53. A compound as claimed by any one of claims 51, 52,and 53 wherein n is
 1. 54. A compound as claimed by any one of claims51, 52, and 53 wherein n is
 2. 55. A compound of Formula Ic andpharmaceutically acceptable salts, solvates and hydrates thereof:

Wherein: n is 1, 2, 3, or 4; R₁ is H, a C1-C4 alkyl, phenyl or C1-C4haloalkyl; R₂ are each, independently, H, a C1-C6 alkyl, a C1-C4 alkoxy,an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, ortogether with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthyl; R₃ are each, independently, H, a C1-C6alkyl, a C1-C4 alkoxy, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, anaryl, or a cycloalkyl; R₄ is a C1-C4 alkyl; R₅ are each, independently,H, a substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that at least one R₅ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl; R14 issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl; R15 is substituted or unsubstituted (CH₂); and R16 is acidbioisosteres.
 56. A compound of claim 55 wherein R14 is Wherein R₇ areeach, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxyl, heterocycle, or a cycloalkyl; and R₈ areeach, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, Heterocyclic or each R₈ takentogether with the phenyl to which they are attached are benzodioxolyl.57. A compound of claim 55 wherein R14 is:

wherein R₇ are each, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, ahalo, C1-C4 haloalkyl, C1-C4 haloalkoxyl, heterocycle, or a cycloalkyl;and R₈ are each, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, ahalo, C1-C4 haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, Heterocyclic oreach R₈ taken together with the phenyl to which they are attached arebenzodioxolyl.
 58. A compound as claimed by any one of claims 55, 56,and 57 wherein n is
 1. 59. A compound as claimed by any one of claims55, 56, and 57 wherein n is
 2. 60. A compound as claimed by any one ofclaims 55, 56, 57, 58, and 59 wherein R16 is tetrazole.
 61. A compoundas claimed by any one of claims 56, 57, 58, 59, and 60 wherein R₇ areeach, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxyl, heterocycle, or a cycloalkyl; and R₈ areeach, independently, H, a C1-C4 alkyl, a C1-C4 alkoxy, a halo, C1-C4haloalkyl, C1-C4 haloalkoxy, a cycloalkyl, or each R₈ taken togetherwith the phenyl to which they are attached are benzodioxolyl.